Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells

Abstract

Peritoneal metastasis is a distinct pathologic characteristic of advanced epithelial ovarian cancer (EOC), which is the most deadly disease of the female reproductive tract. The inflammatory environment of the peritoneum in EOC contains abundant macrophages, activated thrombin, and thrombin-associated receptors. However, little is known about the mechanism by which the thrombin-macrophages interaction contributes to tumor invasion and metastasis. We investigated the phenotype and cytokine/chemokine expression of thrombin-treated peripheral blood monocytes (MOs)/macrophages, it was found that the phenotype of MOs was altered toward a TAM-like macrophage CD163(high)IL-10(high)CCL18(high)IL-8(high) after thrombin stimulation. By Matrigel invasion assay, the conditioned medium of thrombin-stimulated MOs accelerated remarkable invasion of ES-2, SKOV3, and HO-8910, which was similar to invasive cell numbers of ascites stimuli (P< 0.05) and higher than MOs medium alone (P < 0.05). IL-8 was proposed as the major chemoattractant mediating EOC invasion based on MOs mRNA and protein expression profiling. It was observed that anti IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner. Increased transcriptional activation of NF-kappaB p50/p65 was identified in thrombin-treated MOs. This study provided insight the role of thrombin in the regulation of EOC peritoneal invasion via "educating" MOs.

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Production of CCL17, CCL1, chemokine (C-X-C motif) ligand-13 (CXCL13) and CXCL8 (IL-8) has been proven to be associated with an M2a, M2b, M2c and M2d monocyte activation program, respectively, and are parts of mononuclear phagocyte-mediated regulatory circuits of innate and adaptive immunity (Mills et al, 2000;Sironi et al, 2006;Martinez et al, 2008;Duluc et al, 2009;Wang et al, 2010;Zhang et al, 2010a). As shown in Figure 5c, CCL17 levels markedly increased whereas CCL1 did not show apparent change upon M-CSF þ MCP-1, LXA 4 and ANXA1 administration.…”

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…Alterations in cytokine production activate a tumor-associated macrophage (TAM) M2 immunosuppressive phenotype, which is representative of those found in ovarian tumors (23). Polarization of monocytes and macrophages toward an M2 phenotype, which is marked by an increased expression of CD163, IL-10, CCL18, IL-8, chemokine (C-C motif) receptor 2 (CCR2), and chemokine (C-X-C motif) receptor 2 (CXCR2), can be stimulated by coagulation factor XII (FXII) or thrombin (24,25). Interestingly, when treated with either FXII or thrombin, conditioned medium (CM) from TAMs increased ovarian cancer cell invasiveness, with IL-8 being identified as the major chemoattractant mediating this invasion (24,25).…”

“…Polarization of monocytes and macrophages toward an M2 phenotype, which is marked by an increased expression of CD163, IL-10, CCL18, IL-8, chemokine (C-C motif) receptor 2 (CCR2), and chemokine (C-X-C motif) receptor 2 (CXCR2), can be stimulated by coagulation factor XII (FXII) or thrombin (24,25). Interestingly, when treated with either FXII or thrombin, conditioned medium (CM) from TAMs increased ovarian cancer cell invasiveness, with IL-8 being identified as the major chemoattractant mediating this invasion (24,25). Several lines of evidence indicate that activation of the M2 phenotype can also be induced by CM from EOC cells (26), or more specifically, leukemia inhibitory factor (LIF), IL-6, and colony stimulating factor-1 (CSF-1; ref.…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…Nearly every move of malignant cells is accompanied by some function of thrombin, a major player in cancer dissemination that can modify tumor cell behavior either directly through its receptors (protease-activated receptors, PARs) or indirectly by generating fibrin matrices [2,3]. Thrombin enhances tumor invasive potential locally and contributes to cancer cell relocation and seeding [4][5][6][7][8][9][10][11][12][13][14][15]. A prothrombotic state is characteristic for advanced and metastatic cancers [10,11,16,17], and enzymatically active thrombin is reportedly present on surgically excised tumor specimens, including malignant melanoma [reviewed in 3].…”

“…Thrombin enhances tumor invasive potential locally and contributes to cancer cell relocation and seeding [4][5][6][7][8][9][10][11][12][13][14][15]. A prothrombotic state is characteristic for advanced and metastatic cancers [10,11,16,17], and enzymatically active thrombin is reportedly present on surgically excised tumor specimens, including malignant melanoma [reviewed in 3]. Additionally, hirudin, a highly specific thrombin inhibitor, markedly suppresses tumor seeding into the blood, implantation, and spontaneous metastasis in a mouse model, which prolongs survival [13,[18][19][20].…”