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Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options

Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic... Clin Exp Metastasis (2016) 33:401–416 DOI 10.1007/s10585-016-9791-0 REVIEW AR TICLE Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options 1 1,2 1 1 • • • • Nina Sluiter Erienne de Cuba Riom Kwakman Geert Kazemier 2,4 1,3 Gerrit Meijer Elisabeth Atie te Velde Received: 7 December 2015 / Accepted: 7 April 2016 / Published online: 13 April 2016 The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Peritoneal dissemination is diagnosed in to be less relevant in tumour cell adhesion in the context of 10–25 % of colorectal cancer patients. Selected patients peritoneal metastases. Based on currently available data, are treated with cytoreductive surgery and hyperthermic sLe and MUC16 are the most promising prognostic intraperitoneal chemotherapy. For these patients, earlier biomarkers for colorectal peritoneal metastases that may diagnosis, optimised selection criteria and a personalised help improve patient selection. Different adhesion mole- approach are warranted. Biomarkers could play a crucial cules appear expressed in haematogenous and transcoe- role here. However, little is known about possible candi- lomic spread, indicating two different attachment dates. Considering tumour cell adhesion as a key step in processes. However, our extensive assessment of available peritoneal dissemination, we aim to provide an overview of literature reveals that knowledge on metastasis-specific the functional importance of adhesion molecules in peri- genes and their possible candidates is far from complete. toneal dissemination and discuss the prognostic, diagnostic and therapeutic options of these candidate biomarkers. A Keywords Peritoneal metastases  Colorectal cancer systematic literature search was conducted according to the Hipec  Adhesion  Predictive biomarkers  Prognosis PRISMA guidelines. In 132 in vitro, ex vivo and in vivo studies published between 1995 and 2013, we identified Abbreviations twelve possibly relevant adhesion molecules in various CRC Colorectal carcinoma cancers that disseminate peritoneally. The most studied PM Peritoneal metastases molecules in tumour cell adhesion are integrin a2b1, PMP Pseudomyxoma peritonei CD44 s and MUC16. Furthermore, L1CAM, EpCAM, ECM Extracellular matrix x x MUC1, sLe and Le , chemokine receptors, Betaig-H3 and uPA Urokinase plasminogen activator uPAR might be of clinical importance. ICAM1 was found MDR1 Multidrug resistance 1 polypeptide MRP2 Multidrug resistance protein 2 ICAM1 Intercellular adhesion molecule VCAM1 Vascular cell adhesion molecule & Elisabeth Atie te Velde e.tevelde@vumc.nl L1CAM L1 cell adhesion molecule NRP1 Neuropilin 1 Department of Surgery, VU University Medical Centre, a sLe Sialyl Lewis a De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands Le Lewis x Department of Pathology, VU University Medical Centre, x sLe Sialyl Lewis x De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands MUC16 Mucin 16 Department of Surgical Oncology, VU University Medical MUC1 Mucin 1 Centre, De Boelelaan 1117, 1081 HV Amsterdam, EpCAM Epithelial cell adhesion molecule The Netherlands CXCR4 Chemokine (C-X-C) motif receptor 4 Present Address: Department of Pathology, Antoni van uPAR Urokinase receptor Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, Beta ig-h3 Beta induced gene-h3 1066 CX Amsterdam, The Netherlands 123 402 Clin Exp Metastasis (2016) 33:401–416 CX3CL1 Chemokine (C-X3-C motif) ligand 1 surgery-induced tumour spill and upregulation of adhesion IGF-1 Insulin-like growth factor 1 molecules due to post-operative inflammation [9, 20, 23]. HIF-1a Hypoxia-inducible factor 1-alpha Thus, in several groups of patients, tumour cell adhesion to the peritoneum appears to be pivotal in peritoneal dis- semination. Molecules responsible for adhesion might therefore be promising biomarkers that can be used in Introduction diagnosis, prognosis and therapy of PM. Considering tumour cell adhesion as a key step in the formation of PM Colorectal cancer (CRC) is the third most common cancer [16, 24], we aimed to provide an overview of the functional worldwide [1]. Approximately half of CRC patients importance of several attachment markers and to subse- develop distant metastasis, mainly through haematogenous quently evaluate their roles in diagnosis, prognosis and dissemination to the liver [2, 3]. 10–25 % of CRC patients therapy. eventually develop peritoneal metastases (PM) [3, 4] and in up to 25 % of these patients the peritoneum is the only site of metastasis [4, 5]. Typically, untreated PM are associated Methods with poor survival rates, even when treated with modern systemic chemotherapy [6–8]. Literature search Macroscopic complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy A systematic literature search was conducted using the (HIPEC) is the preferred therapeutic strategy for patients PubMed database of the U.S. National library of Medicine with isolated PM [9, 10], resulting in a 5 year survival rate (medline and pre-medline). Table 1 shows the breakdown equal to that of patients undergoing resection for colorectal of search terms and Boolean combinations. liver metastases (35–45 %) [11, 12] and a median survival of 33 months [6, 13, 14]. Inclusion- and exclusion criteria Despite the success of CRS and HIPEC, this treatment has morbidity and mortality rates of 15–34 and 5 % All full-text papers, in English, published between January respectively [5, 6, 11, 15]. Therefore, selection of those 1995 and January 2013 were considered in order to identify patients that will benefit most from this treatment is of as many important adhesion molecules as possible. For this utmost importance. Other challenges in this field are earlier purpose, in vitro, ex vivo and in vivo studies on PM from diagnosis and a more personalised approach, indicating that colorectal, ovarian, gastric and pancreatic cancer as well as the choice of treatment should depend on a cancer’s pseudomyxoma peritonei (PMP) were assessed. These specific biology instead of a ‘one size fits all’ approach types of cancer all disseminate to the peritoneum and can [16]. Based on the hypothesis that the clinical behaviour of be treated with CRS and HIPEC. Literature on PM from PM in CRC is dictated by biological mechanisms, read- CRC is scarce. As such, literature on other malignancies outs of biological information (i.e., biomarkers) are very disseminating to the peritoneum may contain important promising aids in addressing these clinical needs. information. Irrespective of the specific epithelial malig- More specifically, understanding molecular mechanisms nancy, cancer cells disseminate to the peritoneum theo- entails knowledge on molecules contributing to peritoneal retically following the same stepwise process [16]. dissemination. Peritoneal dissemination is considered to be Although the first steps, i.e. detachment from the primary a multistep process in which tumour cells must detach from tumour, gaining motility and evading anoikis, might differ their primary tumour, gain motility and evade anoikis. between these cancers in respect to several molecules, Once a viable, free cancer cell is present in the peritoneal cancer cells of these types of cancer have to attach to the cavity, adherence to the peritoneal surface is required in peritoneal surface to form a peritoneal deposit [16]. order to ultimately invade the peritoneum, proliferate and Accordingly, the same molecular mechanisms might be form PM [16]. important in these cancers and the same interventions Accordingly, the presence of free-floating cancer cells in might be useful in preventing peritoneal dissemination. No the peritoneal cavity is known to increase the risk of reviews and case-reports were included. Other papers were peritoneal dissemination [9, 17–20]. Hence, exfoliation of incorporated by manually cross-referencing from publica- cancer cells into the peritoneal cavity might lead to PM tions retrieved in the initial search. formation in patients presenting with CRC growing An additional review was conducted when deemed through the serosa (T4 stage) [9, 21, 22]. Also patients necessary. When studies overlapped or were duplicated, undergoing abdominal surgery have an increased risk of the articles with the most complete data on tumour cell PM formation, possibly through the combination of 123 Clin Exp Metastasis (2016) 33:401–416 403 Table 1 Search strategy Cancer types Peritoneal metastases Adhesion molecules Cancer AND AND Carcinoma AND Peritoneal Attachment Colorectal Peritoneum Adherence Colon Mesothelium AND Adhesion AND a a Rectal Metastasis Molecule Gastric Peritoneal carcinomatosis Cell adhesion molecules a a Pancreas Pseudomyxoma Peritonei Cell adhesion Pancreatic Peritoneal neoplasms/secondary Pseudomyxoma peritonei OR Colorectal neoplasms Stomach neoplasms Pancreatic neoplasms Ovarian neoplasms Mesh term adhesion to the peritoneum were retained. Figure 1 depicts The above-mentioned studies not only support the role the literature search and the selection process. of integrin a2b1 in tumour cell attachment to the peri- toneum, but also suggest that integrin blocking might be a useful strategy for prevention and treatment of PM. In vivo Results studies suggested a role for antibodies against integrin b1 chains in prevention of colorectal [46], gastric [28, 45] and The key mechanism in PM formation is adherence of pancreatic [47] tumour cell adhesion to (traumatised) malignant cells to the peritoneal surface. Figure 2 illus- peritoneum. Furthermore, the NF-jB inhibitor dehydrox- trates the process of peritoneal dissemination. Figure 3 ymethylepoxyquinomicin (DHMEQ) reduced expression depicts the main interactions responsible for tumour cell of integrin b1 and a2 chains and was effective, both adhesion to the peritoneum. Below, the functional and in vitro and in vivo, in preventing PM formation from clinical importance of the adhesion molecules will be gastric cancer [48]. For this purpose, other compounds that discussed. diminish integrin b1 chain expression, such as phospho- lipids [49], endostatin and simvastatin [42, 50] might be Integrins and integrin ligands effective as well and are interesting to pursue further. Although some studies describe a less prominent role for Integrins integrin b1 chains in PM formation [38, 51, 52], the majority of published literature showed the opposite. Lit- Integrins belong to the superfamily of cell adhesion erature on several other subunits only concerns their roles receptors. This family consists of 24 members, each of in vitro [34, 39–41, 47, 53, 54]. Their roles in vivo, which is a heterodimer composed of a and b subunits [25]. therefore, remain unclear. In particular, integrin b1[26–30] and integrin a2[26–29, 31, 32] chains were shown to be upregulated in cancer cells Integrin ligands with high peritoneal seeding potential. Multiple in vitro and ex vivo blocking experiments with ovarian [26, 27, 33– Multiple in vitro studies have indicated that the main 42], gastric [28, 31, 43–45], colon [46] and pancreatic [30, mesothelial ligands participating in the interaction with 47] cancer cells further endorse the roles of integrin a2b1 integrins are the extracellular matrix (ECM) components in cancer cell attachment to the peritoneum. Besides vitronectin [39, 47, 52, 54, 55], fibronectin [27, 30, 34, 40, mediating adhesion of free-floating tumour cells, integrin 41, 45], laminin [27, 30, 34, 40, 41, 44, 45, 56, 57] and a2b1 might also be important in the adhesion of ovarian collagen I and IV [27, 30, 34, 40, 41, 45]. Adherence of cancer cell aggregates (i.e. spheroids) to the peritoneum, in tumour cells to ECM components occurs in several ways. this way promoting PM formation [40, 41]. First, free tumour cells might enter the submesothelial 123 404 Clin Exp Metastasis (2016) 33:401–416 Fig. 1 PRISMA flow chart for inclusion of the studies [152] compartment at places of peritoneal discontinuity, for coupling of adriamycin to the laminin-5 peptide sequence example places that consist of milky spots [58] or places SWKLPPS, as it increased its in vitro anticancer activity where discontinuity is induced by surgery [23, 46, 59]. [61]. Secondly, tumour cells can induce apoptosis of mesothelial cells [59]. Also, the ECM might be exposed after inflam- Proteoglycans matory mediators induce contraction of mesothelial cells and disruption of intercellular junctions [59]. These ECM CD44 components might serve as treatment targets as well, since blocking them with antibodies and peptide sequences can The CD44 molecule is a cell-surface proteoglycan partic- reduce tumour cell adhesion. For example, the fibronectin ipating in cell–cell interaction, cell adhesion and cell amino acid sequence RGDS and the laminin sequence migration [62]. In particular, CD44 isoforms originating YIGSR inhibited in vitro and in vivo peritoneal dissemi- from alternative splicing are thought to be important in nation from gastric and ovarian cancer [26, 57, 60]. tumour metastasis. The molecule is expressed on Another possible therapeutic option in gastric cancer is mesothelial cells and several types of cancer cells (Fig. 3). 123 Clin Exp Metastasis (2016) 33:401–416 405 Fig. 2 An overview of the essential steps in peritoneal dissemination. The exact molecular mechanisms in tumour cell adhesion to the peritoneum are shown in Fig. 3. Possible therapeutic options focussing on adhesion molecules are shown in Fig. 4 Its overexpression in gastric [29], ovarian [27] and in targets. In vivo blocking of CD44 s prevented PM in pancreatic [30, 63] cancer with high peritoneal seeding ovarian, gastric and pancreatic cancer [28, 30, 60, 68]. potential indicates a putative role for CD44 in PM forma- Other molecules contributing to CD44 mediated cell tion. In vitro and ex vivo blocking experiments in several adhesion might also serve as therapeutic targets, e.g. types of cancer illustrated the role of CD44 as adhesion urokinase plasminogen activator (uPA), multidrug resis- molecule in PM formation [44, 64–70] and particularly tance 1 polypeptide (MDR1) and multidrug resistance indicated a role for the CD44 s splice variant [28, 30, 70]. protein 2 (MRP2) [75]. A third option is inhibiting CD44 Concluding from in vitro, ex vivo and in vivo studies, this glycosylation, because this process is possibly involved in molecule predominantly acts by binding to the ECM pro- CD44 mediated adhesion [66]. The CD44 s splice variant teoglycan hyaluronan [28, 64, 65, 67, 71]. has, despite its role in PM, an uncertain prognostic and CD44 and CD44 s mediated adhesion to hyaluronan diagnostic value [76–80]. might partially be responsible for augmented cancer cell Although—theoretically—blocking the CD44 ligand adhesion during post-operative inflammatory conditions. hyaluronan might prevent peritoneal dissemination, its During this response, reactive oxygen species (ROS) [72, therapeutic value is controversial: both tumour promoting 73] and cytokines, for example TGF-b1, IL-1b and TNF-a and tumour repressing effects were reported after blocking [72, 74], are generated that upregulate CD44 expression CD44 intraperitoneally with hyaluronan [81–83]. and may also be responsible for the expression of other Intraperitoneal application of the hyaluronan-degrading adhesion molecules [69]. enzyme hyaluronidase, however, does yield promising Due to its suggested function in PM, CD44 s and its in vitro results [28, 34, 64, 65]. Hyaluronidase possibly acts ligands hyaluronan are theoretically attractive therapeutic by degradation of mesothelial-associated hyaluronan, 123 406 Clin Exp Metastasis (2016) 33:401–416 Fig. 3 Adhesive interactions mediating tumour cell adhesion to the ovarian and pancreatic cancer cells [95]; d expressed on ovarian peritoneum. a Especially a2b1 expressed on colorectal [46], ovarian cancer cells [98–100]; e expressed on ovarian [40, 93, 122, 123] and [26, 27, 33–42, 149], gastric [28, 31, 43–45, 150] and pancreatic [30, pancreatic [122] cancer cells; f expressed on ovarian cancer cells 47, 151] cancer cells; b especially CD44 and CD44 s expressed on [141]; g expressed on ovarian cancer cells [55]; h expressed on colorectal [64], ovarian [27, 34, 65–67, 70, 76, 77, 90], gastric [28, ovarian cancer cells [93, 105] 29, 78] and pancreatic [30] cancer cells; c expressed on colorectal, thereby preventing hyaluronan from interacting with CD44 chondroitin sulfate proteoglycans, such as heparin, heparin on tumour cells. Another strategy is improving sulfate, dermatan sulfate, chondroitin glycosaminoglycans, chemotherapeutic agent delivery to malignant cells by heparitinase, chondroitinase ABC, or methylumbelliferyl coupling them to hyaluronan. In vivo, promising results xyloside, inhibit ovarian [27, 28, 53, 90] and colorectal were seen for intraperitoneal use of hyaluronan bound [91] cancer cell adhesion to ECM components, blocking cisplatin [84] and hyaluronate (ONCOFID-P) [85] bound to these proteoglycans could be a promising therapeutic paclitaxel in ovarian cancer and for hyaluronan (ONCO- option. FID-S) bound to camptothecin (SN38) in CRC [86]. Lastly, in vitro and in vivo experiments indicated a possible role Immunoglobulin superfamily for adhesion barriers, such as seprafilm and hyalurobarrier, in inhibiting peritoneal dissemination [82, 87–89]. The immunoglobulin superfamily is a large group of cell adhesion proteins, which include intercellular adhesion Other proteoglycans molecule 1 (ICAM 1), vascular cell adhesion molecule 1 (VCAM 1) and L1 cell adhesion molecule (L1CAM) [2, Several other proteoglycans have been described in tumour 92]. cell adhesion to the peritoneum. The proteoglycans syn- decan-1, syndecan-2, syndecan-4, glypican-1 and glypican- ICAM1 3 were upregulated in gastric cancer with high in vitro and in vivo peritoneal seeding potential [90], suggesting a role ICAM1 is a cell surface molecule typically expressed on for these molecules in peritoneal dissemination. Consid- endothelial cells, cells of the immune system, cancer cells ering that several compounds blocking heparan sulfate and [42, 69, 72, 74, 93, 94] and mesothelial cells [69, 72–74, 123 Clin Exp Metastasis (2016) 33:401–416 407 93, 94]. Ziprin et al. [95] demonstrated in vitro tumour cell Blood group antigen proteins adhesion to the peritoneum to be mediated by the inter- action between mesothelial ICAM1 and CD43 (sialo- Several blood group antigens and related structures are phorin) on colorectal, ovarian and pancreatic cancer cells. expressed on tumour cells [28, 30, 102–104], including sialyl Lewis a (sLe , a blood group antigen), Lewis x and This interaction might be important under postoperative x x inflammatory conditions, as the inflammatory mediators sialyl Lewis x (Le and sLe , two blood group antigen x x related structures). However, only Le [93, 105] and sLe TNFa [69, 72, 74, 94], IL-1a [72], IL-1b [72], IL-6 [69] and ROS [73] enhanced ICAM1 expression and stimulated [28, 30, 33, 106] appear to mediate tumour cell adhesion by interacting with mesothelial E-selectin [106]. Although PM formation. Thus, theoretically, anti-ICAM1 antibodies [42, 69] or ICAM1 downregulation with heparin [94] and in vitro and in vivo antibody experiments made the con- simvastatin treatment [42] may be used in prevention of tribution of sLe unlikely [28, 30, 33, 102], in vivo PM PM under inflammatory conditions. However, several formation from pancreatic cancer was inhibited after x a in vitro studies on the role of ICAM1 as an adhesion decreasing sLe and sLe biosynthesis by blocking fuco- molecule in PM did not show reproducible findings [42, 69, syltransferase 3 (FUT3) [107]. 73, 94]. Surprisingly, an in vivo study in gastric cancer Despite its debatable role in tumour cell adhesion to the peritoneum, sLe detection using immunohistochemistry even indicated that ICAM1 possibly inhibits PM formation due to ICAM1/LFA1 mediated mononuclear cell recruit- [104], immunocytology [103] or immunoassays in serum [108] correlated to the presence of PM, peritoneal recur- ment [96]. These contradictory findings make ICAM1 a dubious therapeutic target. rence [109, 110] and poor prognosis [103, 108–112]. In the diagnostic and prognostic field, especially serum and VCAM1 peritoneal lavage levels of CA19-9, a monoclonal antibody against sLe , were shown to be predictive. However, due to The membrane protein VCAM1 mediates leukocyte-en- its low sensitivity and contradictory results in patients with dothelial cell adhesion and signal transduction [97]. The gastric cancer, CRC and PMP [80, 103, 104, 108, 109, mesothelial VCAM1 is possibly responsible for tumour cell 111–120], CA19-9 is not yet qualified for clinical use as a adhesion by interacting with integrin a1b1 and a4b7on single marker. Nevertheless, CA19-9 levels are possibly valuable in combination with other markers, for example tumour cells [93]. Enhanced VCAM1 expression induced by TNF-a,ILb [72, 74] and ROS [73] might contribute to CEA [118–120]. the increased risk of PM formation after surgery. Accord- ingly, downregulating this molecule with anti-VCAM1 Mucins antibodies [42, 71] or simvastatin [42] might prevent peritoneal dissemination. Members of the mucin family are either present as secreted or as transmembrane proteins. Both forms are believed to L1CAM be involved in inflammation and cancer [121]. When it comes to peritoneal spread, Mucin 16 (MUC16) is con- L1CAM is described in various processes contributing to sidered the most important member of this family. In vitro tumour progression, such as differentiation, proliferation, and in vivo studies suggested that cancer cell adhesion to migration, invasion and tumour cell adhesion [98]. Its the peritoneum partly relies on the interaction between upregulation on ovarian cancer cells with high peritoneal MUC16 on ovarian cancer cells and mesothelin on seeding potential indicates a role for L1CAM in PM for- mesothelial cells [122–126]. This interaction is probably mation. In this process, as suggested by in vitro and in vivo mediated by the N-linked oligosaccharides of MUC16. ovarian cancer experiments, it probably mediates adhesion Theoretically, blocking these oligosaccharides with lectins to the peritoneum by interacting with mesothelial neu- is an attractive therapeutic option [123]. In diagnosing PM, ropilin 1 (NRP1) [99]. Although L1CAM has not yet been preoperative MUC16 serum levels in gastric cancer proven to be valuable in the prognostic and diagnostic field patients showed sensitivities ranging from 38.6 to 55 % [100], several therapeutic strategies targeting this molecule and specificities between 93.9 and 100 % [113–115, 127, might be promising. One option might be antibody treat- 128]. However, the prognostic value of MUC16 remains ment, which reduced in vivo PM formation from ovarian inconclusive [80, 127–129]. cancer without producing side effects [98]. Another in vivo MUC1 is another mucin described in PM and is ovarian cancer study indicated possible therapeutic rele- expressed on cancer cells [130–133]. It is questionable as vance for radioimmunotherapy combining anti-L1CAM to whether this mucin has a role in the attachment phase, antibodies (chCE7 and L1-11A) with Cu-radiotherapy since it does not bind mesothelin [122]. Accordingly, the [101]. 123 408 Clin Exp Metastasis (2016) 33:401–416 role of MUC1 in clinical settings is so far not convincing Lastly, beta ig-h3 is an adhesion molecule expressed on [133, 134]. mesothelial cells. Upregulation is associated with increased in vitro gastric cancer cell adhesion and the presence of PM Epithelial cell adhesion molecule (EPCAM) [142], suggesting a role for this molecule in PM. Further- more, in an in vitro ovarian cancer model, peritoneal EpCAM is a homotypic calcium independent cell adhesion cells—but not tumour cells—showed high beta ig-h3 molecule not belonging to one of the previously mentioned levels. This molecule thereby significantly increased groups of molecules [135]. Its expression on cancer cells ovarian cancer cell adhesion to peritoneal cells, which [98] and its upregulation in PM from gastric cancer [136] could be blocked with a beta ig-h3 neutralising antibody suggest a function for this molecule in PM. Its role as [143]. adhesion molecule in PM, however, was not confirmed by in vivo antibody experiments in ovarian cancer [98]. In contrast, studies on the therapeutic value of EpCAM Discussion were promising, indicating that this molecule might pro- mote peritoneal dissemination through other functions. The present study was designed to identify molecules from This is illustrated by treatment with the bispecific antibody literature that mediate tumour cell adhesion to the peri- anti-EpCAM 9 anti-CD3 that eradicated PM from ovarian toneum and to evaluate their roles in diagnosis, prognosis cancer in mice by reactivating tumour-resident T-cells and therapy of PM. Targeting adhesion molecules may not [137]. The bispecific (anti-EpCAM x anti-CD3) trifunc- only prevent tumour cell adhesion and eventually tumour tional antibody Catumaxomab was investigated as outgrowth in patients at high risk for peritoneal dissemi- monotherapy in a phase I/II study, in which this compound nation but the expression of adhesion molecules on tumour was shown to be relatively safe and possibly effective in cells also allows us to use therapies targeting adhesion gastric, colorectal and pancreatic cancer [138]. Concerning molecules in existing peritoneal carcinomatosis (Table 2; its possible diagnostic and prognostic value, data on Fig. 4). Hence, advancing studies on the therapeutic and EpCAM is inconsistent [103, 139]. diagnostic value of adhesion molecules seems a very promising and rational way for optimising and personal- ising treatment of patients presenting with peritoneally Other molecules of interest metastasised CRC. In PM formation, the roles of CD44 s, integrin a2b1 and Several less frequently studied molecules possibly con- MUC16 appeared to be well investigated. Interestingly, tribute to tumour cell adhesion as well. These are chemo- integrin a2b1 is not the typical integrin that binds to ECM kine receptors, transforming growth factor beta induced components. There might be several explanations for this gene-h3 (beta ig-h3) and urokinase receptor (uPAR). discrepancy. First, according to the available literature Although literature on the molecules described in this tumour cells show upregulation of mainly the a2b1 sub- section suggest that they contribute to cancer cell adhesion units, meaning that the overall expression profile of inte- to the peritoneum, further research should confirm this grin subunits might be different from the profile expressed assumption. by non-cancer cells. Consequently, interactions observed The chemokine (C-X3-C motif) receptor 1 (CX3CR1) is between tumour cells and mesothelial cells might differ as expressed by ovarian cancer cells and was shown to well. Secondly, as described in the result sections, literature mediate in vitro tumour cell adhesion to mesothelial cells on several other subunits only concerns their roles in vitro. by interacting with mesothelial chemokine (C-X3-C motif) Their roles in vivo, therefore, remain unclear. Due to their ligand 1 (CX3CL1) [140]. Expression of another chemo- in vitro and ex vivo adhesive functions, L1CAM, proteo- kine, chemokine (C-X-C) motif receptor 4 (CXCR4), is glycans, betaig-H3 and uPAR might contribute to peri- expressed on both mesothelial and cancer cells and corre- toneal dissemination as well. However, their exact lates to worse survival rates in ovarian cancer patients. functions and clinical possibilities have to be elucidated. In vitro and in vivo blocking of CXCR4 with its antagonist Accordingly, in vitro, ex vivo and in vivo antibody ADM3100 was thereby shown to inhibit PM formation experiments should be developed to assess their adhesive [141]. potential. Furthermore, while two systematic reviews sup- uPAR might also be relevant in PM formation and is port our findings on most adhesion molecules [16, 59], detected at the interaction sites of ovarian carcinoma cells most literature regarding the involvement of adhesion and mesothelial cells. In vitro experiments indicated that molecules in PM yields contradictory findings. This may be uPAR mediates tumour cell adhesion by interacting with related to heterogeneity of published methods and varying mesothelial vitronectin [55]. sample sizes. In diagnosis and prognosis of PM, detection 123 Clin Exp Metastasis (2016) 33:401–416 409 Table 2 Summary of targets with possible clinical implication in PM of colorectal, ovarian, gastric and pancreatic cancer and PMP Target in Prognostic relevance Diagnostic relevance Possible therapeutic implications PM Integrins Yes Not clear Promising Higher expression of avb3 correlated to Antibodies against integrin a2 and b1 worse prognosis [30] and ECM components [26–28, 30, 31, 33–47] Peptide sequences of ECM components [26, 57, 60] NF-jB inhibitor (DHMEQ) [48] Phospholipids [49] Adriamycin bound to SWKLPPS, intraperitoneal [61] CD44 Yes Dubious [76, 78, 79] Promising Higher CD44 s expression correlated to Antibodies against CD44 and CD44 s worse survival [77, 78] [28, 30, 44, 60, 64–70] Hyaluronidase, intraperitoneal [28, 34, 64, 65] Adhesion barriers [82, 87–89] Cisplatin [84], paclitaxel [85]or campthotecin [86] bound to hyaluronan VCAM1 Not clear Not clear Dubious, blocking VCAM1 leads theoretically to less PM [42, 71] ICAM1 Not clear Not clear Dubious, blocking ICAM1 leads theoretically to less PM [42, 69, 73, 94, 96] L1CAM Dubious [100]No[100] Highly experimental Antibodies [98] Cu-radiotherapy combined with antibodies, intraperitoneal [101] Blood Yes Yes Highly experimental group CA19-9 levels in serum and peritoneal CA19-9 levels in serum and peritoneal Antibodies against Le [105] antigens fluid [80, 103, 104, 108, 109, 111, 112, fluid [103, 104, 108, 109, 113, 114, Blocking FUT3 [107] 116] 117–120] MUC16 Dubious [80, 127–129] Yes Highly experimental MUC16 levels in serum and peritoneal Antibodies [124] lavage [113–115, 127, 128] MUC1 PT-PCR [132] Blocking mesothelin [122, 123, 125] Anti-MUC1 antibody (C595) combined with docetaxel [130] EpCAM Dubious [103, 140]No[103, 140] Promising Bispecific antibodies EpCAM/CD3 [137] Catuxomab monotherapy, intraperitoneal [138] Chemokine Not clear Not clear Highly experimental receptors Antibodies against CX3CR1 and CX3CL1 [140] ADM3100 [141] uPAR Not clear Not clear Highly experimental Antibodies [55] Beta ig-h3 Not clear Not clear Highly experimental Antibodies [143] The value of the adhesion molecules is regarded dubious when data on these molecules are severely contradictory or sufficient adequate data is lacking 123 410 Clin Exp Metastasis (2016) 33:401–416 Fig. 4 Most promising therapeutic options in prevention (left) and treatment (right) of peritoneal dissemination: 1 anti-integrin a2b1 antibodies; 2 peptide sequences; 3 anti-CD44 antibodies; 4 hyaluronan bound to cytostatic agents; 5 catumaxomab, a trifunctional antibody with binding sites for EpCAM, T-cells and accessory cells. (Color figure online) of MUC16 and blood group antigens might be useful. Prior enter the circulation or the peritoneal cavity respectively. to clinical implementation, however, extensive validation Cancer cells, carried by the blood stream or floating in the of these molecules is necessary. Validation in well-defined peritoneal cavity must evade immune defences in order to patient cohorts is also required for EpCAM, integrin a2b1 reach their host organ. At the site of the host organ, and CD44, molecules that have emerged as possibly useful adhesive interactions between the organ and cancer cells therapeutic targets (Table 2; Fig. 4). Remarkably, while are required for the development of a metastasis [2, 16, 59]. EpCAM showed therapeutic significance in ex vivo and To disseminate to the liver, tumour cells have to adhere to in vivo experiments, its role in in vitro adhesion to the endothelial cells lining the hepatic sinusoids. Interactions peritoneum was not confirmed. This discrepancy might be between tumour cells and endothelial cells that are thought attributable to the finding that EpCAM carries out multiple to be important for liver dissemination consist of CD44 functions, including cell adhesion, cellular signaling, binding to hyaluronan, the blood group antigens sLea and migration, proliferation and differentiation [135, 144–146]. sLex binding to selectins and mucins binding to ECM As such, the combination of these mechanisms, as opposed molecules [2]. This review, however, did not identify blood to only a single function (i.e. adhesion), might be of greater group antigens and E-selectin to be important in peritoneal importance in promoting PM. dissemination. Additionally, L1CAM, proteoglycans, The role of adhesion in haematogenous metastases has betaig-H3 and uPAR might contribute to PM formation, been described in several literature studies. Bird et al. although these molecules were not described in the for- (2006) [2] focused on the development of liver metastases mation of liver metastases. Thus, we propose that from CRC. In both haematogenous spread and spread haematogenous and transcoelomic spread differ in respect across the peritoneal cavity—i.e. transcoelomic spread, to several adhesion molecules. So far, no literature has cancer cells first must detach from the primary tumour to described the exact differences between the mechanisms 123 Clin Exp Metastasis (2016) 33:401–416 411 resulting in liver metastases from CRC and PM from CRC. molecules required for adhesion, a process that could be Difference in adhesion mechanisms can be assumed, since visualised using green fluorescent protein. The previously cancer cells have to attach to different kind of cells: to described steps should be repeated in an environment mesothelial cells in peritoneal dissemination and to reminiscing a surgery-induced environment by addition of endothelial cells in hepatic spread. These different cells interleukins. In this way, several possible candidates can be may express different molecules, making different cell–cell identified that mediate tumour-mesothelial adhesion in interactions necessary for adhesion. Expression of mole- both a surgical and non-surgical setting. These candidates cules depends on signalling molecules present in the should be further studied using antibody blocking in environment, and thus may differ between the peritoneal functional assays and animal models. Prior to clinical surface and the hepatic sinusoids. For example, one study implication, potential diagnostic, prognostic and thera- showed insulin-like growth factor 1 (IGF-1) and hypoxia- peutic value of the identified markers should be validated inducible factor 1-alpha (HIF-1a) to be exclusively over- in well-defined patient cohorts. Further studies should expressed in PM and not in liver metastases [147]. Dif- reduce the risk of bias associated with evaluation of ference in growth factors and angiogenic factors might molecular markers, for example by minimising differences induce different expression patterns in endothelial and in sample handling. It is thereby important to increase the mesothelial cells. reproducibility of individual studies using a split-sample Several studies stress the importance of new molecular for independent validation [148]. Ultimately, increasing targets to improve therapy and selection of patients with PM reproducibility of genome-wide studies and extensive val- of CRC [8, 13, 14]. The adhesion molecules EpCAM, a2b1 idation of possible biomarkers could lead to major advan- and CD44 s were seen to mediate tumour cell adhesion to ces in our understanding of metastasis-specific genes and the peritoneum and might be particularly useful in the pre- their clinical possibilities. For CRC patients with PM, the vention of minimal residual disease in high-risk patients, gained knowledge on the diagnostic and therapeutic such as patients with T4 colon tumours [21, 22]. In addition, options of biomarkers will potentially lead to earlier blocking tumour cell adhesion in the perioperative period diagnosis and a more personalised, or even preventive, may be effective in preventing peritoneal dissemination approach and ultimately to better outcomes. [23]. A preventive HIPEC procedure might possibly be of Compliance with ethical standards additional value in high stage CRC [13]. With respect to a more personalised approach, blocking specific interactions Conflicts of interest None. between the mesothelial lining and tumour cell could be of even greater benefit in patients at high risk of peritoneal Open Access This article is distributed under the terms of the Crea- tive Commons Attribution 4.0 International License (http://creative tumour spread. After blocking interactions between the commons.org/licenses/by/4.0/), which permits unrestricted use, peritoneal surface and tumour cells, tumours cells may die distribution, and reproduction in any medium, provided you give because of anoikis [16]. Furthermore, most tumour cells appropriate credit to the original author(s) and the source, provide a link circulating in the peritoneal cavity are rapidly removed by to the Creative Commons license, and indicate if changes were made. the immune system [23]. 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Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options

Clinical & Experimental Metastasis , Volume 33 – Apr 13, 2016

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0262-0898
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10.1007/s10585-016-9791-0
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Abstract

Clin Exp Metastasis (2016) 33:401–416 DOI 10.1007/s10585-016-9791-0 REVIEW AR TICLE Adhesion molecules in peritoneal dissemination: function, prognostic relevance and therapeutic options 1 1,2 1 1 • • • • Nina Sluiter Erienne de Cuba Riom Kwakman Geert Kazemier 2,4 1,3 Gerrit Meijer Elisabeth Atie te Velde Received: 7 December 2015 / Accepted: 7 April 2016 / Published online: 13 April 2016 The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Peritoneal dissemination is diagnosed in to be less relevant in tumour cell adhesion in the context of 10–25 % of colorectal cancer patients. Selected patients peritoneal metastases. Based on currently available data, are treated with cytoreductive surgery and hyperthermic sLe and MUC16 are the most promising prognostic intraperitoneal chemotherapy. For these patients, earlier biomarkers for colorectal peritoneal metastases that may diagnosis, optimised selection criteria and a personalised help improve patient selection. Different adhesion mole- approach are warranted. Biomarkers could play a crucial cules appear expressed in haematogenous and transcoe- role here. However, little is known about possible candi- lomic spread, indicating two different attachment dates. Considering tumour cell adhesion as a key step in processes. However, our extensive assessment of available peritoneal dissemination, we aim to provide an overview of literature reveals that knowledge on metastasis-specific the functional importance of adhesion molecules in peri- genes and their possible candidates is far from complete. toneal dissemination and discuss the prognostic, diagnostic and therapeutic options of these candidate biomarkers. A Keywords Peritoneal metastases  Colorectal cancer systematic literature search was conducted according to the Hipec  Adhesion  Predictive biomarkers  Prognosis PRISMA guidelines. In 132 in vitro, ex vivo and in vivo studies published between 1995 and 2013, we identified Abbreviations twelve possibly relevant adhesion molecules in various CRC Colorectal carcinoma cancers that disseminate peritoneally. The most studied PM Peritoneal metastases molecules in tumour cell adhesion are integrin a2b1, PMP Pseudomyxoma peritonei CD44 s and MUC16. Furthermore, L1CAM, EpCAM, ECM Extracellular matrix x x MUC1, sLe and Le , chemokine receptors, Betaig-H3 and uPA Urokinase plasminogen activator uPAR might be of clinical importance. ICAM1 was found MDR1 Multidrug resistance 1 polypeptide MRP2 Multidrug resistance protein 2 ICAM1 Intercellular adhesion molecule VCAM1 Vascular cell adhesion molecule & Elisabeth Atie te Velde e.tevelde@vumc.nl L1CAM L1 cell adhesion molecule NRP1 Neuropilin 1 Department of Surgery, VU University Medical Centre, a sLe Sialyl Lewis a De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands Le Lewis x Department of Pathology, VU University Medical Centre, x sLe Sialyl Lewis x De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands MUC16 Mucin 16 Department of Surgical Oncology, VU University Medical MUC1 Mucin 1 Centre, De Boelelaan 1117, 1081 HV Amsterdam, EpCAM Epithelial cell adhesion molecule The Netherlands CXCR4 Chemokine (C-X-C) motif receptor 4 Present Address: Department of Pathology, Antoni van uPAR Urokinase receptor Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, Beta ig-h3 Beta induced gene-h3 1066 CX Amsterdam, The Netherlands 123 402 Clin Exp Metastasis (2016) 33:401–416 CX3CL1 Chemokine (C-X3-C motif) ligand 1 surgery-induced tumour spill and upregulation of adhesion IGF-1 Insulin-like growth factor 1 molecules due to post-operative inflammation [9, 20, 23]. HIF-1a Hypoxia-inducible factor 1-alpha Thus, in several groups of patients, tumour cell adhesion to the peritoneum appears to be pivotal in peritoneal dis- semination. Molecules responsible for adhesion might therefore be promising biomarkers that can be used in Introduction diagnosis, prognosis and therapy of PM. Considering tumour cell adhesion as a key step in the formation of PM Colorectal cancer (CRC) is the third most common cancer [16, 24], we aimed to provide an overview of the functional worldwide [1]. Approximately half of CRC patients importance of several attachment markers and to subse- develop distant metastasis, mainly through haematogenous quently evaluate their roles in diagnosis, prognosis and dissemination to the liver [2, 3]. 10–25 % of CRC patients therapy. eventually develop peritoneal metastases (PM) [3, 4] and in up to 25 % of these patients the peritoneum is the only site of metastasis [4, 5]. Typically, untreated PM are associated Methods with poor survival rates, even when treated with modern systemic chemotherapy [6–8]. Literature search Macroscopic complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy A systematic literature search was conducted using the (HIPEC) is the preferred therapeutic strategy for patients PubMed database of the U.S. National library of Medicine with isolated PM [9, 10], resulting in a 5 year survival rate (medline and pre-medline). Table 1 shows the breakdown equal to that of patients undergoing resection for colorectal of search terms and Boolean combinations. liver metastases (35–45 %) [11, 12] and a median survival of 33 months [6, 13, 14]. Inclusion- and exclusion criteria Despite the success of CRS and HIPEC, this treatment has morbidity and mortality rates of 15–34 and 5 % All full-text papers, in English, published between January respectively [5, 6, 11, 15]. Therefore, selection of those 1995 and January 2013 were considered in order to identify patients that will benefit most from this treatment is of as many important adhesion molecules as possible. For this utmost importance. Other challenges in this field are earlier purpose, in vitro, ex vivo and in vivo studies on PM from diagnosis and a more personalised approach, indicating that colorectal, ovarian, gastric and pancreatic cancer as well as the choice of treatment should depend on a cancer’s pseudomyxoma peritonei (PMP) were assessed. These specific biology instead of a ‘one size fits all’ approach types of cancer all disseminate to the peritoneum and can [16]. Based on the hypothesis that the clinical behaviour of be treated with CRS and HIPEC. Literature on PM from PM in CRC is dictated by biological mechanisms, read- CRC is scarce. As such, literature on other malignancies outs of biological information (i.e., biomarkers) are very disseminating to the peritoneum may contain important promising aids in addressing these clinical needs. information. Irrespective of the specific epithelial malig- More specifically, understanding molecular mechanisms nancy, cancer cells disseminate to the peritoneum theo- entails knowledge on molecules contributing to peritoneal retically following the same stepwise process [16]. dissemination. Peritoneal dissemination is considered to be Although the first steps, i.e. detachment from the primary a multistep process in which tumour cells must detach from tumour, gaining motility and evading anoikis, might differ their primary tumour, gain motility and evade anoikis. between these cancers in respect to several molecules, Once a viable, free cancer cell is present in the peritoneal cancer cells of these types of cancer have to attach to the cavity, adherence to the peritoneal surface is required in peritoneal surface to form a peritoneal deposit [16]. order to ultimately invade the peritoneum, proliferate and Accordingly, the same molecular mechanisms might be form PM [16]. important in these cancers and the same interventions Accordingly, the presence of free-floating cancer cells in might be useful in preventing peritoneal dissemination. No the peritoneal cavity is known to increase the risk of reviews and case-reports were included. Other papers were peritoneal dissemination [9, 17–20]. Hence, exfoliation of incorporated by manually cross-referencing from publica- cancer cells into the peritoneal cavity might lead to PM tions retrieved in the initial search. formation in patients presenting with CRC growing An additional review was conducted when deemed through the serosa (T4 stage) [9, 21, 22]. Also patients necessary. When studies overlapped or were duplicated, undergoing abdominal surgery have an increased risk of the articles with the most complete data on tumour cell PM formation, possibly through the combination of 123 Clin Exp Metastasis (2016) 33:401–416 403 Table 1 Search strategy Cancer types Peritoneal metastases Adhesion molecules Cancer AND AND Carcinoma AND Peritoneal Attachment Colorectal Peritoneum Adherence Colon Mesothelium AND Adhesion AND a a Rectal Metastasis Molecule Gastric Peritoneal carcinomatosis Cell adhesion molecules a a Pancreas Pseudomyxoma Peritonei Cell adhesion Pancreatic Peritoneal neoplasms/secondary Pseudomyxoma peritonei OR Colorectal neoplasms Stomach neoplasms Pancreatic neoplasms Ovarian neoplasms Mesh term adhesion to the peritoneum were retained. Figure 1 depicts The above-mentioned studies not only support the role the literature search and the selection process. of integrin a2b1 in tumour cell attachment to the peri- toneum, but also suggest that integrin blocking might be a useful strategy for prevention and treatment of PM. In vivo Results studies suggested a role for antibodies against integrin b1 chains in prevention of colorectal [46], gastric [28, 45] and The key mechanism in PM formation is adherence of pancreatic [47] tumour cell adhesion to (traumatised) malignant cells to the peritoneal surface. Figure 2 illus- peritoneum. Furthermore, the NF-jB inhibitor dehydrox- trates the process of peritoneal dissemination. Figure 3 ymethylepoxyquinomicin (DHMEQ) reduced expression depicts the main interactions responsible for tumour cell of integrin b1 and a2 chains and was effective, both adhesion to the peritoneum. Below, the functional and in vitro and in vivo, in preventing PM formation from clinical importance of the adhesion molecules will be gastric cancer [48]. For this purpose, other compounds that discussed. diminish integrin b1 chain expression, such as phospho- lipids [49], endostatin and simvastatin [42, 50] might be Integrins and integrin ligands effective as well and are interesting to pursue further. Although some studies describe a less prominent role for Integrins integrin b1 chains in PM formation [38, 51, 52], the majority of published literature showed the opposite. Lit- Integrins belong to the superfamily of cell adhesion erature on several other subunits only concerns their roles receptors. This family consists of 24 members, each of in vitro [34, 39–41, 47, 53, 54]. Their roles in vivo, which is a heterodimer composed of a and b subunits [25]. therefore, remain unclear. In particular, integrin b1[26–30] and integrin a2[26–29, 31, 32] chains were shown to be upregulated in cancer cells Integrin ligands with high peritoneal seeding potential. Multiple in vitro and ex vivo blocking experiments with ovarian [26, 27, 33– Multiple in vitro studies have indicated that the main 42], gastric [28, 31, 43–45], colon [46] and pancreatic [30, mesothelial ligands participating in the interaction with 47] cancer cells further endorse the roles of integrin a2b1 integrins are the extracellular matrix (ECM) components in cancer cell attachment to the peritoneum. Besides vitronectin [39, 47, 52, 54, 55], fibronectin [27, 30, 34, 40, mediating adhesion of free-floating tumour cells, integrin 41, 45], laminin [27, 30, 34, 40, 41, 44, 45, 56, 57] and a2b1 might also be important in the adhesion of ovarian collagen I and IV [27, 30, 34, 40, 41, 45]. Adherence of cancer cell aggregates (i.e. spheroids) to the peritoneum, in tumour cells to ECM components occurs in several ways. this way promoting PM formation [40, 41]. First, free tumour cells might enter the submesothelial 123 404 Clin Exp Metastasis (2016) 33:401–416 Fig. 1 PRISMA flow chart for inclusion of the studies [152] compartment at places of peritoneal discontinuity, for coupling of adriamycin to the laminin-5 peptide sequence example places that consist of milky spots [58] or places SWKLPPS, as it increased its in vitro anticancer activity where discontinuity is induced by surgery [23, 46, 59]. [61]. Secondly, tumour cells can induce apoptosis of mesothelial cells [59]. Also, the ECM might be exposed after inflam- Proteoglycans matory mediators induce contraction of mesothelial cells and disruption of intercellular junctions [59]. These ECM CD44 components might serve as treatment targets as well, since blocking them with antibodies and peptide sequences can The CD44 molecule is a cell-surface proteoglycan partic- reduce tumour cell adhesion. For example, the fibronectin ipating in cell–cell interaction, cell adhesion and cell amino acid sequence RGDS and the laminin sequence migration [62]. In particular, CD44 isoforms originating YIGSR inhibited in vitro and in vivo peritoneal dissemi- from alternative splicing are thought to be important in nation from gastric and ovarian cancer [26, 57, 60]. tumour metastasis. The molecule is expressed on Another possible therapeutic option in gastric cancer is mesothelial cells and several types of cancer cells (Fig. 3). 123 Clin Exp Metastasis (2016) 33:401–416 405 Fig. 2 An overview of the essential steps in peritoneal dissemination. The exact molecular mechanisms in tumour cell adhesion to the peritoneum are shown in Fig. 3. Possible therapeutic options focussing on adhesion molecules are shown in Fig. 4 Its overexpression in gastric [29], ovarian [27] and in targets. In vivo blocking of CD44 s prevented PM in pancreatic [30, 63] cancer with high peritoneal seeding ovarian, gastric and pancreatic cancer [28, 30, 60, 68]. potential indicates a putative role for CD44 in PM forma- Other molecules contributing to CD44 mediated cell tion. In vitro and ex vivo blocking experiments in several adhesion might also serve as therapeutic targets, e.g. types of cancer illustrated the role of CD44 as adhesion urokinase plasminogen activator (uPA), multidrug resis- molecule in PM formation [44, 64–70] and particularly tance 1 polypeptide (MDR1) and multidrug resistance indicated a role for the CD44 s splice variant [28, 30, 70]. protein 2 (MRP2) [75]. A third option is inhibiting CD44 Concluding from in vitro, ex vivo and in vivo studies, this glycosylation, because this process is possibly involved in molecule predominantly acts by binding to the ECM pro- CD44 mediated adhesion [66]. The CD44 s splice variant teoglycan hyaluronan [28, 64, 65, 67, 71]. has, despite its role in PM, an uncertain prognostic and CD44 and CD44 s mediated adhesion to hyaluronan diagnostic value [76–80]. might partially be responsible for augmented cancer cell Although—theoretically—blocking the CD44 ligand adhesion during post-operative inflammatory conditions. hyaluronan might prevent peritoneal dissemination, its During this response, reactive oxygen species (ROS) [72, therapeutic value is controversial: both tumour promoting 73] and cytokines, for example TGF-b1, IL-1b and TNF-a and tumour repressing effects were reported after blocking [72, 74], are generated that upregulate CD44 expression CD44 intraperitoneally with hyaluronan [81–83]. and may also be responsible for the expression of other Intraperitoneal application of the hyaluronan-degrading adhesion molecules [69]. enzyme hyaluronidase, however, does yield promising Due to its suggested function in PM, CD44 s and its in vitro results [28, 34, 64, 65]. Hyaluronidase possibly acts ligands hyaluronan are theoretically attractive therapeutic by degradation of mesothelial-associated hyaluronan, 123 406 Clin Exp Metastasis (2016) 33:401–416 Fig. 3 Adhesive interactions mediating tumour cell adhesion to the ovarian and pancreatic cancer cells [95]; d expressed on ovarian peritoneum. a Especially a2b1 expressed on colorectal [46], ovarian cancer cells [98–100]; e expressed on ovarian [40, 93, 122, 123] and [26, 27, 33–42, 149], gastric [28, 31, 43–45, 150] and pancreatic [30, pancreatic [122] cancer cells; f expressed on ovarian cancer cells 47, 151] cancer cells; b especially CD44 and CD44 s expressed on [141]; g expressed on ovarian cancer cells [55]; h expressed on colorectal [64], ovarian [27, 34, 65–67, 70, 76, 77, 90], gastric [28, ovarian cancer cells [93, 105] 29, 78] and pancreatic [30] cancer cells; c expressed on colorectal, thereby preventing hyaluronan from interacting with CD44 chondroitin sulfate proteoglycans, such as heparin, heparin on tumour cells. Another strategy is improving sulfate, dermatan sulfate, chondroitin glycosaminoglycans, chemotherapeutic agent delivery to malignant cells by heparitinase, chondroitinase ABC, or methylumbelliferyl coupling them to hyaluronan. In vivo, promising results xyloside, inhibit ovarian [27, 28, 53, 90] and colorectal were seen for intraperitoneal use of hyaluronan bound [91] cancer cell adhesion to ECM components, blocking cisplatin [84] and hyaluronate (ONCOFID-P) [85] bound to these proteoglycans could be a promising therapeutic paclitaxel in ovarian cancer and for hyaluronan (ONCO- option. FID-S) bound to camptothecin (SN38) in CRC [86]. Lastly, in vitro and in vivo experiments indicated a possible role Immunoglobulin superfamily for adhesion barriers, such as seprafilm and hyalurobarrier, in inhibiting peritoneal dissemination [82, 87–89]. The immunoglobulin superfamily is a large group of cell adhesion proteins, which include intercellular adhesion Other proteoglycans molecule 1 (ICAM 1), vascular cell adhesion molecule 1 (VCAM 1) and L1 cell adhesion molecule (L1CAM) [2, Several other proteoglycans have been described in tumour 92]. cell adhesion to the peritoneum. The proteoglycans syn- decan-1, syndecan-2, syndecan-4, glypican-1 and glypican- ICAM1 3 were upregulated in gastric cancer with high in vitro and in vivo peritoneal seeding potential [90], suggesting a role ICAM1 is a cell surface molecule typically expressed on for these molecules in peritoneal dissemination. Consid- endothelial cells, cells of the immune system, cancer cells ering that several compounds blocking heparan sulfate and [42, 69, 72, 74, 93, 94] and mesothelial cells [69, 72–74, 123 Clin Exp Metastasis (2016) 33:401–416 407 93, 94]. Ziprin et al. [95] demonstrated in vitro tumour cell Blood group antigen proteins adhesion to the peritoneum to be mediated by the inter- action between mesothelial ICAM1 and CD43 (sialo- Several blood group antigens and related structures are phorin) on colorectal, ovarian and pancreatic cancer cells. expressed on tumour cells [28, 30, 102–104], including sialyl Lewis a (sLe , a blood group antigen), Lewis x and This interaction might be important under postoperative x x inflammatory conditions, as the inflammatory mediators sialyl Lewis x (Le and sLe , two blood group antigen x x related structures). However, only Le [93, 105] and sLe TNFa [69, 72, 74, 94], IL-1a [72], IL-1b [72], IL-6 [69] and ROS [73] enhanced ICAM1 expression and stimulated [28, 30, 33, 106] appear to mediate tumour cell adhesion by interacting with mesothelial E-selectin [106]. Although PM formation. Thus, theoretically, anti-ICAM1 antibodies [42, 69] or ICAM1 downregulation with heparin [94] and in vitro and in vivo antibody experiments made the con- simvastatin treatment [42] may be used in prevention of tribution of sLe unlikely [28, 30, 33, 102], in vivo PM PM under inflammatory conditions. However, several formation from pancreatic cancer was inhibited after x a in vitro studies on the role of ICAM1 as an adhesion decreasing sLe and sLe biosynthesis by blocking fuco- molecule in PM did not show reproducible findings [42, 69, syltransferase 3 (FUT3) [107]. 73, 94]. Surprisingly, an in vivo study in gastric cancer Despite its debatable role in tumour cell adhesion to the peritoneum, sLe detection using immunohistochemistry even indicated that ICAM1 possibly inhibits PM formation due to ICAM1/LFA1 mediated mononuclear cell recruit- [104], immunocytology [103] or immunoassays in serum [108] correlated to the presence of PM, peritoneal recur- ment [96]. These contradictory findings make ICAM1 a dubious therapeutic target. rence [109, 110] and poor prognosis [103, 108–112]. In the diagnostic and prognostic field, especially serum and VCAM1 peritoneal lavage levels of CA19-9, a monoclonal antibody against sLe , were shown to be predictive. However, due to The membrane protein VCAM1 mediates leukocyte-en- its low sensitivity and contradictory results in patients with dothelial cell adhesion and signal transduction [97]. The gastric cancer, CRC and PMP [80, 103, 104, 108, 109, mesothelial VCAM1 is possibly responsible for tumour cell 111–120], CA19-9 is not yet qualified for clinical use as a adhesion by interacting with integrin a1b1 and a4b7on single marker. Nevertheless, CA19-9 levels are possibly valuable in combination with other markers, for example tumour cells [93]. Enhanced VCAM1 expression induced by TNF-a,ILb [72, 74] and ROS [73] might contribute to CEA [118–120]. the increased risk of PM formation after surgery. Accord- ingly, downregulating this molecule with anti-VCAM1 Mucins antibodies [42, 71] or simvastatin [42] might prevent peritoneal dissemination. Members of the mucin family are either present as secreted or as transmembrane proteins. Both forms are believed to L1CAM be involved in inflammation and cancer [121]. When it comes to peritoneal spread, Mucin 16 (MUC16) is con- L1CAM is described in various processes contributing to sidered the most important member of this family. In vitro tumour progression, such as differentiation, proliferation, and in vivo studies suggested that cancer cell adhesion to migration, invasion and tumour cell adhesion [98]. Its the peritoneum partly relies on the interaction between upregulation on ovarian cancer cells with high peritoneal MUC16 on ovarian cancer cells and mesothelin on seeding potential indicates a role for L1CAM in PM for- mesothelial cells [122–126]. This interaction is probably mation. In this process, as suggested by in vitro and in vivo mediated by the N-linked oligosaccharides of MUC16. ovarian cancer experiments, it probably mediates adhesion Theoretically, blocking these oligosaccharides with lectins to the peritoneum by interacting with mesothelial neu- is an attractive therapeutic option [123]. In diagnosing PM, ropilin 1 (NRP1) [99]. Although L1CAM has not yet been preoperative MUC16 serum levels in gastric cancer proven to be valuable in the prognostic and diagnostic field patients showed sensitivities ranging from 38.6 to 55 % [100], several therapeutic strategies targeting this molecule and specificities between 93.9 and 100 % [113–115, 127, might be promising. One option might be antibody treat- 128]. However, the prognostic value of MUC16 remains ment, which reduced in vivo PM formation from ovarian inconclusive [80, 127–129]. cancer without producing side effects [98]. Another in vivo MUC1 is another mucin described in PM and is ovarian cancer study indicated possible therapeutic rele- expressed on cancer cells [130–133]. It is questionable as vance for radioimmunotherapy combining anti-L1CAM to whether this mucin has a role in the attachment phase, antibodies (chCE7 and L1-11A) with Cu-radiotherapy since it does not bind mesothelin [122]. Accordingly, the [101]. 123 408 Clin Exp Metastasis (2016) 33:401–416 role of MUC1 in clinical settings is so far not convincing Lastly, beta ig-h3 is an adhesion molecule expressed on [133, 134]. mesothelial cells. Upregulation is associated with increased in vitro gastric cancer cell adhesion and the presence of PM Epithelial cell adhesion molecule (EPCAM) [142], suggesting a role for this molecule in PM. Further- more, in an in vitro ovarian cancer model, peritoneal EpCAM is a homotypic calcium independent cell adhesion cells—but not tumour cells—showed high beta ig-h3 molecule not belonging to one of the previously mentioned levels. This molecule thereby significantly increased groups of molecules [135]. Its expression on cancer cells ovarian cancer cell adhesion to peritoneal cells, which [98] and its upregulation in PM from gastric cancer [136] could be blocked with a beta ig-h3 neutralising antibody suggest a function for this molecule in PM. Its role as [143]. adhesion molecule in PM, however, was not confirmed by in vivo antibody experiments in ovarian cancer [98]. In contrast, studies on the therapeutic value of EpCAM Discussion were promising, indicating that this molecule might pro- mote peritoneal dissemination through other functions. The present study was designed to identify molecules from This is illustrated by treatment with the bispecific antibody literature that mediate tumour cell adhesion to the peri- anti-EpCAM 9 anti-CD3 that eradicated PM from ovarian toneum and to evaluate their roles in diagnosis, prognosis cancer in mice by reactivating tumour-resident T-cells and therapy of PM. Targeting adhesion molecules may not [137]. The bispecific (anti-EpCAM x anti-CD3) trifunc- only prevent tumour cell adhesion and eventually tumour tional antibody Catumaxomab was investigated as outgrowth in patients at high risk for peritoneal dissemi- monotherapy in a phase I/II study, in which this compound nation but the expression of adhesion molecules on tumour was shown to be relatively safe and possibly effective in cells also allows us to use therapies targeting adhesion gastric, colorectal and pancreatic cancer [138]. Concerning molecules in existing peritoneal carcinomatosis (Table 2; its possible diagnostic and prognostic value, data on Fig. 4). Hence, advancing studies on the therapeutic and EpCAM is inconsistent [103, 139]. diagnostic value of adhesion molecules seems a very promising and rational way for optimising and personal- ising treatment of patients presenting with peritoneally Other molecules of interest metastasised CRC. In PM formation, the roles of CD44 s, integrin a2b1 and Several less frequently studied molecules possibly con- MUC16 appeared to be well investigated. Interestingly, tribute to tumour cell adhesion as well. These are chemo- integrin a2b1 is not the typical integrin that binds to ECM kine receptors, transforming growth factor beta induced components. There might be several explanations for this gene-h3 (beta ig-h3) and urokinase receptor (uPAR). discrepancy. First, according to the available literature Although literature on the molecules described in this tumour cells show upregulation of mainly the a2b1 sub- section suggest that they contribute to cancer cell adhesion units, meaning that the overall expression profile of inte- to the peritoneum, further research should confirm this grin subunits might be different from the profile expressed assumption. by non-cancer cells. Consequently, interactions observed The chemokine (C-X3-C motif) receptor 1 (CX3CR1) is between tumour cells and mesothelial cells might differ as expressed by ovarian cancer cells and was shown to well. Secondly, as described in the result sections, literature mediate in vitro tumour cell adhesion to mesothelial cells on several other subunits only concerns their roles in vitro. by interacting with mesothelial chemokine (C-X3-C motif) Their roles in vivo, therefore, remain unclear. Due to their ligand 1 (CX3CL1) [140]. Expression of another chemo- in vitro and ex vivo adhesive functions, L1CAM, proteo- kine, chemokine (C-X-C) motif receptor 4 (CXCR4), is glycans, betaig-H3 and uPAR might contribute to peri- expressed on both mesothelial and cancer cells and corre- toneal dissemination as well. However, their exact lates to worse survival rates in ovarian cancer patients. functions and clinical possibilities have to be elucidated. In vitro and in vivo blocking of CXCR4 with its antagonist Accordingly, in vitro, ex vivo and in vivo antibody ADM3100 was thereby shown to inhibit PM formation experiments should be developed to assess their adhesive [141]. potential. Furthermore, while two systematic reviews sup- uPAR might also be relevant in PM formation and is port our findings on most adhesion molecules [16, 59], detected at the interaction sites of ovarian carcinoma cells most literature regarding the involvement of adhesion and mesothelial cells. In vitro experiments indicated that molecules in PM yields contradictory findings. This may be uPAR mediates tumour cell adhesion by interacting with related to heterogeneity of published methods and varying mesothelial vitronectin [55]. sample sizes. In diagnosis and prognosis of PM, detection 123 Clin Exp Metastasis (2016) 33:401–416 409 Table 2 Summary of targets with possible clinical implication in PM of colorectal, ovarian, gastric and pancreatic cancer and PMP Target in Prognostic relevance Diagnostic relevance Possible therapeutic implications PM Integrins Yes Not clear Promising Higher expression of avb3 correlated to Antibodies against integrin a2 and b1 worse prognosis [30] and ECM components [26–28, 30, 31, 33–47] Peptide sequences of ECM components [26, 57, 60] NF-jB inhibitor (DHMEQ) [48] Phospholipids [49] Adriamycin bound to SWKLPPS, intraperitoneal [61] CD44 Yes Dubious [76, 78, 79] Promising Higher CD44 s expression correlated to Antibodies against CD44 and CD44 s worse survival [77, 78] [28, 30, 44, 60, 64–70] Hyaluronidase, intraperitoneal [28, 34, 64, 65] Adhesion barriers [82, 87–89] Cisplatin [84], paclitaxel [85]or campthotecin [86] bound to hyaluronan VCAM1 Not clear Not clear Dubious, blocking VCAM1 leads theoretically to less PM [42, 71] ICAM1 Not clear Not clear Dubious, blocking ICAM1 leads theoretically to less PM [42, 69, 73, 94, 96] L1CAM Dubious [100]No[100] Highly experimental Antibodies [98] Cu-radiotherapy combined with antibodies, intraperitoneal [101] Blood Yes Yes Highly experimental group CA19-9 levels in serum and peritoneal CA19-9 levels in serum and peritoneal Antibodies against Le [105] antigens fluid [80, 103, 104, 108, 109, 111, 112, fluid [103, 104, 108, 109, 113, 114, Blocking FUT3 [107] 116] 117–120] MUC16 Dubious [80, 127–129] Yes Highly experimental MUC16 levels in serum and peritoneal Antibodies [124] lavage [113–115, 127, 128] MUC1 PT-PCR [132] Blocking mesothelin [122, 123, 125] Anti-MUC1 antibody (C595) combined with docetaxel [130] EpCAM Dubious [103, 140]No[103, 140] Promising Bispecific antibodies EpCAM/CD3 [137] Catuxomab monotherapy, intraperitoneal [138] Chemokine Not clear Not clear Highly experimental receptors Antibodies against CX3CR1 and CX3CL1 [140] ADM3100 [141] uPAR Not clear Not clear Highly experimental Antibodies [55] Beta ig-h3 Not clear Not clear Highly experimental Antibodies [143] The value of the adhesion molecules is regarded dubious when data on these molecules are severely contradictory or sufficient adequate data is lacking 123 410 Clin Exp Metastasis (2016) 33:401–416 Fig. 4 Most promising therapeutic options in prevention (left) and treatment (right) of peritoneal dissemination: 1 anti-integrin a2b1 antibodies; 2 peptide sequences; 3 anti-CD44 antibodies; 4 hyaluronan bound to cytostatic agents; 5 catumaxomab, a trifunctional antibody with binding sites for EpCAM, T-cells and accessory cells. (Color figure online) of MUC16 and blood group antigens might be useful. Prior enter the circulation or the peritoneal cavity respectively. to clinical implementation, however, extensive validation Cancer cells, carried by the blood stream or floating in the of these molecules is necessary. Validation in well-defined peritoneal cavity must evade immune defences in order to patient cohorts is also required for EpCAM, integrin a2b1 reach their host organ. At the site of the host organ, and CD44, molecules that have emerged as possibly useful adhesive interactions between the organ and cancer cells therapeutic targets (Table 2; Fig. 4). Remarkably, while are required for the development of a metastasis [2, 16, 59]. EpCAM showed therapeutic significance in ex vivo and To disseminate to the liver, tumour cells have to adhere to in vivo experiments, its role in in vitro adhesion to the endothelial cells lining the hepatic sinusoids. Interactions peritoneum was not confirmed. This discrepancy might be between tumour cells and endothelial cells that are thought attributable to the finding that EpCAM carries out multiple to be important for liver dissemination consist of CD44 functions, including cell adhesion, cellular signaling, binding to hyaluronan, the blood group antigens sLea and migration, proliferation and differentiation [135, 144–146]. sLex binding to selectins and mucins binding to ECM As such, the combination of these mechanisms, as opposed molecules [2]. This review, however, did not identify blood to only a single function (i.e. adhesion), might be of greater group antigens and E-selectin to be important in peritoneal importance in promoting PM. dissemination. Additionally, L1CAM, proteoglycans, The role of adhesion in haematogenous metastases has betaig-H3 and uPAR might contribute to PM formation, been described in several literature studies. Bird et al. although these molecules were not described in the for- (2006) [2] focused on the development of liver metastases mation of liver metastases. Thus, we propose that from CRC. In both haematogenous spread and spread haematogenous and transcoelomic spread differ in respect across the peritoneal cavity—i.e. transcoelomic spread, to several adhesion molecules. So far, no literature has cancer cells first must detach from the primary tumour to described the exact differences between the mechanisms 123 Clin Exp Metastasis (2016) 33:401–416 411 resulting in liver metastases from CRC and PM from CRC. molecules required for adhesion, a process that could be Difference in adhesion mechanisms can be assumed, since visualised using green fluorescent protein. The previously cancer cells have to attach to different kind of cells: to described steps should be repeated in an environment mesothelial cells in peritoneal dissemination and to reminiscing a surgery-induced environment by addition of endothelial cells in hepatic spread. These different cells interleukins. In this way, several possible candidates can be may express different molecules, making different cell–cell identified that mediate tumour-mesothelial adhesion in interactions necessary for adhesion. Expression of mole- both a surgical and non-surgical setting. These candidates cules depends on signalling molecules present in the should be further studied using antibody blocking in environment, and thus may differ between the peritoneal functional assays and animal models. Prior to clinical surface and the hepatic sinusoids. For example, one study implication, potential diagnostic, prognostic and thera- showed insulin-like growth factor 1 (IGF-1) and hypoxia- peutic value of the identified markers should be validated inducible factor 1-alpha (HIF-1a) to be exclusively over- in well-defined patient cohorts. Further studies should expressed in PM and not in liver metastases [147]. Dif- reduce the risk of bias associated with evaluation of ference in growth factors and angiogenic factors might molecular markers, for example by minimising differences induce different expression patterns in endothelial and in sample handling. It is thereby important to increase the mesothelial cells. reproducibility of individual studies using a split-sample Several studies stress the importance of new molecular for independent validation [148]. Ultimately, increasing targets to improve therapy and selection of patients with PM reproducibility of genome-wide studies and extensive val- of CRC [8, 13, 14]. The adhesion molecules EpCAM, a2b1 idation of possible biomarkers could lead to major advan- and CD44 s were seen to mediate tumour cell adhesion to ces in our understanding of metastasis-specific genes and the peritoneum and might be particularly useful in the pre- their clinical possibilities. For CRC patients with PM, the vention of minimal residual disease in high-risk patients, gained knowledge on the diagnostic and therapeutic such as patients with T4 colon tumours [21, 22]. In addition, options of biomarkers will potentially lead to earlier blocking tumour cell adhesion in the perioperative period diagnosis and a more personalised, or even preventive, may be effective in preventing peritoneal dissemination approach and ultimately to better outcomes. [23]. A preventive HIPEC procedure might possibly be of Compliance with ethical standards additional value in high stage CRC [13]. With respect to a more personalised approach, blocking specific interactions Conflicts of interest None. between the mesothelial lining and tumour cell could be of even greater benefit in patients at high risk of peritoneal Open Access This article is distributed under the terms of the Crea- tive Commons Attribution 4.0 International License (http://creative tumour spread. After blocking interactions between the commons.org/licenses/by/4.0/), which permits unrestricted use, peritoneal surface and tumour cells, tumours cells may die distribution, and reproduction in any medium, provided you give because of anoikis [16]. Furthermore, most tumour cells appropriate credit to the original author(s) and the source, provide a link circulating in the peritoneal cavity are rapidly removed by to the Creative Commons license, and indicate if changes were made. the immune system [23]. 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Published: Apr 13, 2016

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