Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells

PURPOSE: Interleukin-2 (IL-2) and IL-15 receptors have been detected on some murine neoplasms. Accordingly, the expression of these receptors on human uveal melanoma cell lines was examined, and the effect of exogenous IL-2 and -15 on melanoma cell proliferation, susceptibility to natural killer (NK) cell-mediated cytolysis, and sensitivity to apoptosis were assessed. METHODS: Nine human uveal melanoma cell lines and three cell lines from uveal melanoma metastases were tested by flow cytometry for the expression of human IL-2R and -15Ralpha. Melanoma cells were cultured, with or without recombinant human IL-2 or -15, cell proliferation was determined by tritiated thymidine incorporation, and IL-2 and -15 receptor expression was assessed by flow cytometry. The effect of these cytokines on NK activity was evaluated with a standard (51)Cr-release assay. RESULTS: All the melanoma cell lines expressed IL-2R and -15R. IL-2 induced a three- to eightfold upregulation of IL-2R expression in all the melanoma cell lines. Although IL-2 did not affect the proliferation of six of the seven uveal melanoma cell lines, it induced a 32% and 57% increase in the proliferation of both metastatic cell lines. IL-15 induced proliferation on all tested cell lines (4%-68%). Both IL-2 and -15 reduced melanoma cell sensitivity to NK-cell-mediated cytolysis and cisplatin-induced apoptosis. CONCLUSIONS: The results suggest that IL-2 and -15 elaborated by tumor-infiltrating lymphocytes and macrophages may affect the malignant behavior of human uveal melanoma by stimulating proliferation and reducing uveal melanoma cell susceptibility to NK-cell-mediated cytolysis and cisplatin-induced apoptosis.     

Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K

AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines (OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib (EGF-R), everolimus (mTOR), selumetinib (MAPK), trametinib (MAPK) or the alkylphosphocholine erufosine (PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) dye reduction assay after 24h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC50 was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, trametinib, and erufosine significantly decreased cell viability of all OMM cell lines (P<0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation (P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations (P<0.05). Besides an increase of necrotic cells after erufosine treatment (P<0.001), no changes in the number of dead cells for the other substances were observed. CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/mTOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.     

Role of Fas ligand in uveal melanoma-induced liver damage

BACKGROUND: Uveal melanoma, the most common adult intraocular malignancy, metastasizes preferentially to the liver. Areas of cell death surrounding uveal melanoma metastases were observed in the livers of mice. We hypothesized that uveal melanoma cells might express Fas ligand (FasL), facilitating FasL-mediated apoptosis of Fas-expressing hepatocytes. PURPOSE: To determine whether Fas ligand (FasL)-expressing human uveal melanoma cells induce apoptosis of human hepatocytes in vitro and in vivo. METHODS: Human uveal melanoma cell lines were assayed for FasL expression by flow cytometry and immunohistology. A human hepatocyte cell line was assayed for Fas expression by flow cytometry. Apoptosis of hepatocytes was detected by annexin V staining in vitro, and terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in vivo. RESULTS: Human uveal melanoma cell lines expressed FasL, as determined by flow cytometry and immunohistology. Human hepatocytes were Fas-positive by flow cytometry. In vitro, annexin V staining revealed that human uveal melanoma cells induced apoptosis of human hepatocytes. TUNEL staining of liver metastases revealed apoptosis of murine hepatocytes in contact with metastatic human uveal melanoma cells. CONCLUSION: FasL-induced apoptosis of hepatocytes in contact with FasL-positive human uveal melanoma cells may contribute to hepatic failure during metastatic disease.     

Uveal melanoma expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and susceptibility to TRAIL-induced apoptosis

PURPOSE: The study had two purposes: to examine the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors on uveal melanoma cells and metastases arising from uveal melanoma and to determine the susceptibility of uveal melanoma cells to TRAIL-induced apoptosis. METHODS: Nine human uveal melanoma cell lines and three cell lines derived from uveal melanoma metastases were examined for TRAIL receptor expression by flow cytometry. In vitro apoptosis assays were performed to determine the relative susceptibility of uveal melanoma cells to TRAIL-induced apoptosis. Annexin V staining was also used to determine the capacity of either cycloheximide or interferon-beta to enhance TRAIL-induced apoptosis. RESULTS: Five of the nine uveal melanoma cell lines expressed TRAIL-R2 on more than 60% of the cells. All three of the cell lines derived from uveal melanoma metastases expressed TRAIL-R2 on more than 50% of the cells. Cycloheximide exerted a profound effect in enhancing TRAIL-induced apoptosis in all but two of the uveal melanoma cell lines and in all three of the metastases cell lines. Interferon-beta produced a similar enhancement of TRAIL-induced apoptosis, even in cell lines that were previously shown to be resistant. CONCLUSIONS: TRAIL is a potentially useful therapeutic modality for the management of uveal melanomas and their metastases. Moreover, pharmacological agents and biological response modifiers that independently display antineoplastic properties can enhance TRAIL-induced apoptosis in resistant uveal melanoma cells.     

Differential expression of chemokine receptors on uveal melanoma cells and their metastases

PURPOSE: To determine the expression of the chemokine receptors CXCR4 and CCR7 on human uveal melanoma cells and their metastases and the effect of liver-borne factors on the chemotactic responses of uveal melanoma cells. METHODS: Four human uveal melanoma cell lines and three cell lines of uveal melanoma metastases were examined by RT-PCR and flow cytometry for their constitutive expression of CXCR4 and CCR7. The effect of the liver and liver-borne factors on the expression of CXCR4 and CCR7 was determined after intracameral, intrasplenic, and subcutaneous transplantation of uveal melanoma cells in nude mice. Chemotactic responses of melanoma cells to liver-borne factors were determined by in vitro chemotaxis assays using protein extracts of hepatocytes and striated muscle tissue. RESULTS: All the primary uveal melanoma cell lines expressed CXCR4 and CCR7 message and protein, whereas the metastases cell lines expressed little or no chemokine receptor. Extracts of human liver cells stimulated chemotaxis of uveal melanoma cells, which could be inhibited by anti-CXCR4 antibody. Liver-borne factors also induced the downregulation of CXCR4 and CCR7 on uveal melanoma cells. Uveal melanoma cells maintained their high expression of CXCR4 and CCR7 after intracameral transplantation. However, CXCR4 and CCR7 expression was sharply reduced in liver metastases arising from intraocular melanomas. CONCLUSIONS: CXCR4 and CCR7 provide directional migration of uveal melanoma cells toward the liver, the most common site for the formation of uveal melanoma metastases. However, soluble factors elaborated by hepatocytes induce the downregulation of CXCR4 and CCR7 on metastatic uveal melanoma cells.     

PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro

PURPOSE: To assess the expression of PD-L1 on human uveal melanomas and its potential to suppress T-cell function. METHODS: A panel of primary and metastatic uveal melanoma cell lines was evaluated for PD-L1 expression by RT-PCR and flow cytometric analysis. Uveal melanoma-containing eyes were examined for PD-L1 expression by immunohistochemistry. PD-L1 function was tested by coculturing IFN-gamma-pretreated uveal melanoma cells with activated Jurkat T cells for 48 hours and assessing T-cell production of IL-2 by ELISA. RESULTS: Five of the nine primary and one of the five metastatic uveal melanoma cell lines tested constitutively expressed PD-L1 protein at various levels. However, all primary and metastatic uveal melanoma cell lines upregulated PD-L1 expression after stimulation with IFN-gamma. Immunohistochemistry demonstrated that PD-L1 was not expressed by primary uveal melanomas in situ. IL-2 production by activated Jurkat T cells was decreased significantly when the cells were cocultured with IFN-gamma-pretreated uveal melanoma cells. More than 70% of IL-2 production was restored by addition of either anti-PD-L1 or anti-PD-1 antibody to the coculture assays (P < 0.01). CONCLUSIONS: Expression of PD-L1 by uveal melanoma cells regulates T-cell function by suppressing IL-2 production. The results imply that the presence of IFN-gamma in the tumor local microenvironment promotes upregulation of PD-L1 expression by uveal melanoma, which may, in part, promote immune escape by impairing T-cell function. The selective blockade of PD-L1 is a potential strategy in T-cell-based immunotherapy for uveal melanoma.     

反义bcl-2寡核苷酸对体外培养的葡萄膜黑色素瘤细胞多药耐药性的影响

目的：探讨体外培养的葡萄膜黑色素瘤细胞对不同化疗药物的敏感性,并通过反义bcl-2寡核苷酸（bcl-2 antisense oligodeoxynucleotide,bcl-2 AS-ODN）特异阻断bcl-2基因的表达逆转肿瘤耐药性。方法：原代培养葡萄膜黑色素瘤细胞,采用噻唑蓝染色法测定肿瘤细胞对不同浓度的5-氟尿嘧啶、噻替哌、顺铂、阿霉素、长春新碱和氮烯咪胺体外敏感性;通过阳离子脂质体导入bcl-2 AS-ODN,阻断bcl-2基因的表达,利用免疫组化及Western blot法测定肿瘤细胞bcl-2的表达情况,并根据多药相互作用原理测定肿瘤细胞对化疗药物敏感性。结果：葡萄膜黑色素瘤对不同种类的化疗药物均有不同程度的抗药性。Bcl-2 AS-ODN可明显抑制bcl-2基因的表达,并随浓度升高抑制作用增强。Bcl-2AS-ODN与各种化疗药物呈协同作用,能够增加化疗药物对肿瘤细胞的杀伤作用。结论：所选6种化疗药物在临床常用剂量范围对葡萄膜黑色素瘤细胞毒性作用较小,葡萄膜黑色素瘤细胞的多药耐药性与bcl-2基因的高表达有关,bcl-2 AS-ODN能够部分逆转肿瘤细胞的多药耐药性。     

Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma

PURPOSE: The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulinlike growth factor-1 receptor (IGF-1R) and inhibits the growth of uveal melanoma cells in vitro and in vivo. In this study, the authors investigated the efficiency of orally administered PPP on the growth of uveal melanoma xenografts. In addition, they focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established antitumor agents in vitro. METHODS: Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-fluorouracil, and doxorubicin. Cell viability was determined by XTT assay. SCID mice that underwent xenografting with uveal melanoma cells were used to determine antitumor efficacy of oral PPP in vivo. Five mice were used per group. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by Western blotting. RESULTS: PPP was found to be superior to the other antitumor agents in killing uveal melanoma cells in all four cell lines (IC50 < 0.05 microM). Oral PPP inhibited uveal melanoma growth in vivo in OCM-3 (P = 0.03) and OCM-8 (P = 0.01) xenografts and was well tolerated by the animals. PPP decreased VEGF expression in the OCM-1 (P = 0.006) and OCM-8 (P = 0.01) tumors. CONCLUSIONS: Oral PPP was well tolerated in vivo, caused total growth inhibition of uveal melanoma xenografts, and decreased VEGF levels in the tumors.     

Human uveal melanoma cells inhibit the immunostimulatory function of dendritic cells

Dendritic cells are critical for the induction of anti-tumor immunity. Recent studies suggest that some tumors may avoid immune destruction by inhibiting dendritic cell function. In this study, we investigated the effects of uveal melanoma on human dendritic cell phenotype and functions including surface antigen expression, cytokine production, and T cell activation. Dendritic cells were generated in the presence of GM-CSF and IL-4 from peripheral blood mononuclear cells of healthy donors. On day 5 of culture, dendritic cells were co-cultured with human uveal melanoma cells for 24 h, and then purified using magnetic beads. The maturation of dendritic cells was induced by TNF-α and the phenotype of dendritic cells was analyzed by flow cytometry. The expression of dendritic cell markers and antigen presenting cell markers decreased when dendritic cells were co-cultured with uveal melanoma cells. Moreover, co-culture with uveal melanoma cells led to apoptosis of dendritic cells as shown by 1.5-fold increase in surface phosphatidylserine. Also, dendritic cells co-cultured with uveal melanoma showed diminished ability to produce IL-12 and IL-10. Finally, dendritic cells co-cultured with uveal melanoma inhibited the proliferation of allogeneic T cells in mixed lymphocyte reaction. These findings suggest a mechanism by which uveal melanoma escape immune destruction and have significant implications for tumor-pulsed dendritic cell vaccines for the treatment of uveal melanoma.     

Costimulatory molecule expression on human uveal melanoma cells: functional analysis of CD40 and B7-H1

Costimulatory molecules play important roles in regulating T cell function in tumor immunity. In this study, we investigated costimulatory molecule expression on human uveal melanoma cells (a primary culture, and OCM-1, OMM-1 and 92-1 cell lines) and assessed the functional roles of selected costimulatory molecules. Uveal melanoma cells were incubated in the presence or absence of IFN-γ and expression of costimulatory molecules on the cells was measured by flow cytometry. The costimulatory effect of B7-H1-expressing uveal melanoma cells on cytokine production by purified T cells was studied in uveal melanoma/T cell co-culture experiments using a blocking anti-B7-H1 monoclonal antibody (mAb). The functional role of CD40-mediated interactions in modifying immune responses to uveal melanoma cells was assessed in?vitro using recombinant human CD40 ligand (rhCD40L). MHC class I and B7-H1 were consistently detected and further upregulated by IFN-γ stimulation in all human uveal melanoma cell cultures. CD40 was consistently detected and further upregulated by IFN-γ stimulation in primary culture, OCM-1, and OMM-1 but not 92-1. IL-2 production from purified CD3(+) T cells co-stimulated with IFN-γ-treated uveal melanoma cells was significantly enhanced by the addition of anti-B7-H1 mAb. Treatment of primary culture, OCM-1, or OMM-1 with rhCD40L induced or enhanced secretion of chemokines IL-8, MCP-1, IP-10 and RANTES. These results suggest that the expression of B7-H1 on IFN-γ-treated uveal melanoma cells contributes to suppression of T cells by decreasing IL-2 production. In contrast, CD40 expressed on uveal melanoma cells plays an important role in augmenting anti-tumor immunity by stimulating chemokine production. The dual effects of CD40 and B7-H1 may contribute to positive or negative regulation of anti-tumor immune responses to human uveal melanoma.     

Apoptosis inhibitor, survivin, in posterior uveal melanoma: comparison among primary tumors, tumors resistant to brachytherapy, tumors with liver metastases, and liver metastases

PURPOSE: To study the expression of survivin, an apoptosis inhibitor protein, in human posterior uveal melanoma. METHODS: Specimens were divided according to eyes with tumors that were enucleated primarily, those resistant to brachytherapy, eyes from patients with known liver metastases, and liver metastases. RESULTS: There was only low expression of survivin in uveal melanoma. No difference in survivin positive cell counts per high power field (PCC/HPF) were found among tumors that were enucleated primarily (n = 33), tumors with previous brachytherapy (n = 29), tumors with liver metastases (n = 12) or liver metastases (n = 18). Corresponding counts were 11.8 (+/-14.3), 11.8 (+/-16.8), 7.1 (+/-11.2), and 4.7 (+/-8.8) in the four groups, respectively (p > 0.05). Half of the liver metastases showed no staining for survivin. Twenty patients (24%) had tumor-related death at the end of follow-up. CONCLUSIONS: Survivin is expressed in posterior uveal melanomas that were treated by enucleation, as well as in tumors that were previously treated with brachytherapy or liver metastases; however, its expression by immunostaining did not seem with correlate with the tumor biological activity.     

survivin基因的分子生物学特征及眼科研究进展

survivin是凋亡抑制蛋白家族的新成员,其独特的分子结构、组织分布特异性及强大的抗凋亡作用使其逐渐成为肿瘤发病及治疗研究中的一个热点。作为判断肿瘤预后的一个新指标,以及肿瘤靶向治疗的一个新靶点,着重对survivin的分子生物学特性、功能、作用机制以及在眼科研究中的应用作一综述。     

c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target?

PURPOSE: This study was conducted to investigate the expression and functional impact of the proto-oncogene c-kit in uveal melanoma. METHODS: Based on immunohistochemical (IHC) study of paraffin-embedded specimens from 134 uveal melanomas and Western blot analysis on eight fresh-frozen samples the expression of c-kit in uveal melanoma was studied. Furthermore, the phosphorylation of c-kit and the impact of the tyrosine kinase inhibitor STI571 was examined in the three uveal melanoma cell lines OCM-1, OCM-3, and 92-1. RESULTS: Eighty-four of 134 paraffin-embedded samples and six of eight fresh-frozen samples expressed c-kit. c-Kit was strongly expressed and tyrosine phosphorylated in cultured uveal melanoma cells compared with cutaneous melanoma cells. Moreover, in contrast to cutaneous melanoma cell lines c-kit maintained a high phosphorylation level in serum-depleted uveal melanoma cells. No activation-related mutations in exon 11 of the KIT gene were found. On the contrary, expression of the stem cell growth factor (c-kit ligand) was detected in all three uveal melanoma cell lines, suggesting the presence of autocrine (paracrine) stimulation pathways. Treatment of uveal melanoma cell lines with STI571, which blocks c-kit autophosphorylation, resulted in cell death. The IC(50) of the inhibitory effects on c-kit phosphorylation and cell proliferation was of equal size and less than 2.5 microM. CONCLUSIONS: The results confirm that c-kit is vastly expressed in uveal melanoma, suggest that the c-kit molecular pathway may be important in uveal melanoma growth, and point to its use as a target for therapy with STI571.     

Effects of interferon alfa and gamma on human uveal melanoma cells in vitro.

BACKGROUND--Uveal melanoma is a tumour with a high incidence of metastasis and a high mortality rate. Additional therapies to obtain a better local control or an effective treatment of metastases are necessary. Interferons may be applied. METHODS--The effects of human interferon alfa and gamma on proliferation and expression of immunologically important molecules of human uveal melanoma cells in vitro were studied. A propidium iodide assay was used to determine proliferation and immunostaining with monoclonal antibodies was applied to detect changes in antigen expression on two primary uveal melanoma cell lines, Mel 202 and 92-1. RESULTS--Interferon alfa inhibited proliferation of cell line 92-1 at a concentration of 50 IU/ml, but had no effect on cell line Mel 202, while interferon gamma inhibited growth of both cell lines. Only interferon gamma had a visible effect on cell morphology. With respect to the immunomodulatory effects, interferon alfa increased monomorphic HLA class I expression, but did not affect HLA class II expression. Interferon gamma induced not only HLA class I but also class II expression. The effects on HLA expression were locus-specific with the strongest effects observed for HLA-B and DR products. Small differences were observed with respect to the susceptibility of two different melanoma cell lines to antiproliferative effects and to modulation of antigen expression. CONCLUSION--The effects of interferon alfa and gamma on human uveal melanoma cells in vitro suggest a potential role of these cytokines in the treatment of patients with uveal melanoma. In particular, the immunomodulatory effects of these cytokines in vitro imply that treatment of patients with these cytokines might stimulate a beneficial antimelanoma immune response in vivo.     

17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines

PURPOSE: The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been shown to have promising results in antitumor activity through the degradation of the activated V600E mutant of B-Raf (V600E B-Raf) in cutaneous melanoma cell lines. It has different effects, however, on the wild-type form of B-Raf (WT B-Raf), according to the WT B-Raf activation levels in the tumor cells. Uveal melanoma cells express WT B-Raf and only rarely express V600E B-Raf. This study was conducted to investigate the effects of HSP90 inhibition on uveal melanoma cell lines. METHODS: Human uveal melanoma cell lines were treated with the HSP90 inhibitors 17-AAG and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG). Cell proliferation was assessed by MTT staining, and apoptosis was quantified by flow cytometry. Analysis of the expression of HSP90 and activation of the MEK/ERK downstream signaling of B-Raf was performed by Western blot. Effects of the downregulation of the HSP90 cochaperone, cdc37, on cell proliferation and activation of MEK/ERK was investigated by siRNA strategy. RESULTS: The inhibition of HSP90 downregulated B-Raf, decreased cell proliferation, and reduced activation of MEK/ERK in uveal melanoma cell lines expressing WT B-Raf. HSP90 inhibition also reduced the expression of Akt, but the inhibition of Akt had no effect on cell proliferation, ruling out a role of Akt in the 17-AAG-induced inhibition of cell proliferation. The downregulation of cdc37 did not affect MEK/ERK signaling and cell proliferation, demonstrating that the cochaperone was not required for HSP90-controlled stability of B-Raf. c-Kit was also downregulated after HSP90 inhibition. The combination of 17-DMAG with imatinib mesylate, the inhibitor of c-kit, had synergistic inhibitory effects on cell proliferation in WT B-Raf uveal melanoma cell lines. CONCLUSIONS: These results suggest that targeting HSP90 in tandem with c-Kit inhibition may be a promising therapeutic approach to uveal melanoma.     

Secretion of interleukin-6 and prostaglandin E2 during uveal melanoma-monocyte in vitro interactions

Host-tumor interactions in uveal melanoma are not well understood. It is believed that the cytokine interleukin-6 and the lipid mediator autacoid prostaglandin E2 are involved in tumor growth, proliferation, tumor cell survival, and angiogenesis. These cytokines have been shown to be poor prognostic markers in uveal and cutaneous melanoma. In this study, we investigated the levels of interleukin-6 and prostaglandin E2 in monocyte and uveal melanoma conditioned medium. Five human uveal melanoma cell lines (92.1, MKT-BR, OCM-1, SP6.5 and UW-1), and one monocyte cell line (28SC) were seeded in 6 well plates at a concentration of 1 x 10(6)cells ml(-1). After 18 hr melanoma conditioned medium was placed on the monocyte cell line and monocyte conditioned medium was placed on each uveal melanoma cell line. Tumor cells and monocytes incubated in fresh medium after 18 hr were used as controls. Interleukin-6 and prostaglandin E2 levels were determined by immunoassays prior to media transfer and 6, 12, 24, and 36 hr thereafter. In the absence of conditioned medium, neither product showed baseline levels of expression. Interleukin-6 but not prostaglandin E2, which remained undetectable for the duration of the study, showed up-regulation of expression after incubation in conditioned medium. 28SC incubated in melanoma conditioned medium expressed higher levels of interleukin-6 than did uveal melanoma cells incubated in monocyte conditioned medium. In addition each cell line exhibited a distinct pattern of expression with individual cell lines exhibiting peak levels of cytokine production at different time points. The results of this study offer insight into the mechanism by which interleukin 6 may be involved in tumor-host interactions potentially favoring tumor growth, survival, and proliferation.