Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis

Abstract

Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27) cells increased their metastatic ability, specifically to the liver and documented high collagen IV levels in surgical resections of liver metastases from diverse tumor types. Here, we aimed to elucidate the functional relevance of collagen IV to metastatic outgrowth in the liver. Gene expression profiling revealed in M27cells significant increases in the expression of chemokines CCL5 (5.7-fold) and CCL7 (2.6-fold) relative to wild-type cells, and this was validated by qPCR and western blotting. Similarly, in human colon carcinoma KM12C and KM12SM cells with divergent liver-colonizing potentials, CCL7 and CCL5 production correlated with type IV collagen expression and the metastatic phenotype. CCL7 silencing by short hairpin RNA (shRNA) reduced experimental liver metastasis in both cell types, whereas CCL5 silencing reduced metastasis of M27 cells, implicating these cytokines in metastatic expansion in the liver. Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3. Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver. Loss of CCL7 in KM12SM cells was also associated with altered E-cadherin and reduced vimentin and Snail expression, implicating it in epithelial-to-mesenchymal transition in these cells. Moreover, in clinical specimens of colon cancer liver metastases analyzed by immunohistochemistry, CCL5 and CCL7 levels paralleled those of collagen IV. The results identify the chemokines CCL5 and CCL7 as type IV collagen-regulated genes that promote liver metastasis by distinct and complementary mechanisms.

Upregulated Collagen COL10A1 Remodels the Extracellular Matrix and Promotes Malignant Progression in Lung Adenocarcinoma

“…Collagen I, IV and V have been shown to foster adhesion, proliferation, and migration in pancreatic ductal adenocarcinoma (PDAC) ( 29 ). Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis ( 30 ). As far as the progression of breast tumors, collagens appear to straighten and align at the tumor-boundary to facilitate the invasion of the tumor into the surrounding stroma ( 31 ).The collagen family plays an important role in the invasion and metastasis of tumors…”

Down-regulation of TRIB3 inhibits the progression of ovarian cancer via MEK/ERK signaling pathway

“…In pancreatic cancer, researchers have found that the KrasG12D mutation up-regulated the levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) through activating the MEK/ERK pathway inducing regulatory T cells (Tregs) conversion and immunosuppressive [ 44 ]. Furthermore, CCL7 also was regulated by MEK/ERK pathways in many cancers, such as colon cancer cells [ 45 ] and Liver metastases [ 46 ].…”

A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis

“…Expression of collagens in tumor tissues could ignite tumor invasion and metastasis via various pathways. Vaniotis et al found that type IV collagen could induce liver metastasis of lung cancer by increasing CCL5 and CCL7 synthesis [31]. Collagen IV could also activate DDR1 and AKT to promote invasion and migration of myeloid leukemia cells [32].…”