Selectin-driven leukocyte recruitment and chemokines facilitate metastasis

Tumor is a complex tissue composed of malignant and heterogeneous non-malignant cells. Tumor progression is determined by the dynamic interactions between these cells. Soluble factors secreted within the tumor microenvironment stimulate stromal cells and induce infiltration by inflammatory cells. High amounts of monocytes/macrophages, commonly found in various types of malignant cancer are associated with increased tumor cell extravasation and metastasis. A recent study reported that CCL2 recruits inflammatory monocytes to promote metastasis. Concerted action of chemokines and adhesion molecules (selectins) regulates the homing of leukocytes to target sites. However, the role of endogenous (non-tumor derived) selectin ligands in metastasis was not characterized. To study the contribution of endogenous selectin ligands to metastasis, we used Fuc-TVII-/- mice which display defective selectin ligands. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII-/- mice correlated with attenuated metastasis, suggesting the presence of endogenous selectin ligands on monocytes as a prerequisite for their capture at metastatic sites. Adoptive transfer of Fuc-TVII+ monocytes rescued metastasis, corroborating that monocyte recruitment is selectin ligand-dependent. Moreover, decreased CCL2 expression in Fuc-TVII deficient lung was linked to impaired monocyte recruitment, reduced tumor cell survival and attenuated metastasis. This study demonstrated that endogenous selectin ligands mediate the recruitment and activation of monocytes at the metastatic site and thereby facilitate metastasis. To delineate the molecular mechanism governing the effect of CCL2 on metastasis, we used different mouse models. Together with Monika Wolf, we demonstrated that CCR2 expression not only on monocytes, but in particular on the endothelium, is crucial for metastasis. Tumor cell-derived CCL2 induced vascular permeability and enabled efficient tumor cell extravasation via CCR2 signaling. The absence of CCR2 on the endothelium abolished tumor cell extravasation even in the presence of CCR2+ monocytes, highlighting that activation of CCR2 on the endothelium is a prerequisite for tumor cell migration. Collectively, our study identified a novel mechanism for CCL2-dependent metastasis

Metastatic growth progression caused by PSGL-1-mediated recruitment of monocytes to metastatic sites

Tumor cell-derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non-tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII(-/-))-deficient mice. Experimental metastasis of MC-38GFP and Lewis lung (3LL) carcinoma cells was attenuated in Fuc-TVII(-/-) mice, which express minimal amount of selectin ligands. We show that metastasis is dependent on selectin ligands carried on hematopoietic cells. P-selectin glycoprotein ligand-1 (PSGL-1) was identified as the major ligand facilitating monocyte accumulation at metastatic sites. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII(-/-) mice correlated with attenuated metastasis. Adoptive transfer of Fuc-T7(+) monocytes rescued metastasis in Fuc-TVII(-/-) mice, indicating that selectin ligand-dependent recruitment of monocytes is required for cancer progression. Cytokine analysis in metastatic lungs revealed high expression of CCL2 in C57BL/6 mice that was significantly lower in Fuc-TVII(-/-) mice. The absence of monocyte recruitment in Fuc-TVII(-/-) mice correlated with increased apoptosis of tumor cells. Thus, the recruitment of monocytes to metastasizing tumor cells is facilitated by endogenous selectin ligands on monocytes that enable efficient tumor cell survival, extravasation, and metastasis

Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9

BACKGROUND: Invasion of extracellular matrix is a hallmark of malignant tumors. Clamping maneuvers during cancer surgery reduce blood loss, but trigger reperfusion injury (RI). RI increases cancer recurrence in the reperfused organ through up-regulation of matrix metalloproteinase-9 (MMP-9). Interleukin-8 is an important cytokine in RI promoting accumulation of neutrophils, a major source of MMP-9. Volatile anesthetics were demonstrated to reduce RI. We hypothesized that these anesthetics might attenuate MMP-9 up-regulation and consequently tumor cell invasion in RI. METHODS: Isolated human neutrophils (n = 6) were preconditioned with sevoflurane or desflurane, followed by stimulation with interleukin-8, phorbol myristate acetate, or chemokine CXC-ligand 1 (CXCL1) to differentiate intracellular pathways. MMP-9 release and activity were quantified by enzyme-linked immunosorbent assay and zymography, respectively. CXC-receptor-2 (CXCR2) expression and phosphorylation of extracellular signal-regulated kinases 1/2 were assessed by flow cytometry. The impact of MMP-9 on the invasion of neutrophils and MC-38 colon cancer cells was assessed using Matrigel-coated filters (n = 6). RESULTS: Preconditioning reduced interleukin-8-induced MMP-9-release by 41% (±13, 5%, sevoflurane) and 40% (±13%, desflurane). This was also evident following stimulation of CXCR2 with CXCL1. No impact on phosphorylation of extracellular signal-regulated kinases 1/2 and MMP-9 release was observed with receptor-independent stimulation of protein kinase C with phorbol myristate acetate. Preconditioning reduced transmigration of neutrophils and MC-38 tumor cells to baseline levels. DISCUSSION: Volatile anesthetics impair neutrophil MMP-9 release and interfere with pathways downstream of CXCR2, but upstream of protein kinase C. Through down-regulation of MMP-9, volatile anesthetics decrease Matrigel breakdown and reduce subsequent migration of cancer cells in vitro

Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway

Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis