CXCL10 Promotes Invasion-Related Properties in Human Colorectal Carcinoma Cells

Abstract

CXCL10 was recently shown to exert antimalignancy functions by influencing the tumor microenvironment. Here, we have taken a different approach, investigating the effects of CXCL10 directly on tumor-promoting functions in colorectal carcinoma (CRC) cells. CXCL10 expression was detected in preferred metastatic sites of CRC (liver, lungs, and lymph nodes), and its CXCR3 receptor was expressed by eight CRC cell lines (detected: reverse transcription-PCR and/or flow cytometry). Detailed analysis was done on two cell lines derived from primary CRC tumors (SW480, KM12C) and their metastatic descendents (SW620 and KM12SM). The three known variants of CXCR3 (CXCR3-A, CXCR3-B, and CXCR3-alt) were detected in all four cell lines. CXCR3 expression was also observed on colorectal tumor cells in biopsies of CRC patients (immunohistochemistry). CXCL10 and CXCR3 expression were potently induced in CRC cells by Interferon ; and all four CRC cell lines responded to CXCL10 by extracellular signal-regulated kinase 1/2 dephosphorylation. The chemokine did not affect tumor cell growth or angiogenesis-related functions in the tumor cells, such as CXCL8 and vascular endothelial growth factor secretion. Importantly, CXCL10 significantly up-regulated invasion-related properties in CRC cells: It promoted matrix metalloproteinase 9 expression and induced CRC cell migration. Of note, CXCL10-induced migration was detected only in the two metastatic cells and not in their primary counterparts. Also, CXCL10 promoted the adhesion of metastatic cells to laminin. These results suggest that CXCL10 can be exploited by CRC cells toward their progression, thus possibly antagonizing the antimalignancy effects of the chemokine on the tumor microenvironment. Therefore, care should be taken when considering CXCL10 as a therapeutic antitumor modality for CRC treatment. [Cancer Res 2007;67(7):3396-405]

CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model

“…CXCR3 has been identified in biopsies of ovarian and renal cell carcinomas (18,19). Two laboratories have described the expression of CXCR3 in colon cancer (22,24) and observed CXCR3 both in the cytoplasm and plasma membrane of malignant, but not normal, colonic epithelium. CXCR3 expression was strongly correlated with lymph node metastasis.…”

“…The data on the effects of CXCR3 ligands on tumor cell proliferation are contradictory: In some human tumor cells, ligand induces tumor cell proliferation (6,17,22), and in other cells, ligand has no effect on cell growth (24). Some of these differences are likely attributable to the expression of CXCR3 splice variants in different cells (24,26).…”

“…Some of these differences are likely attributable to the expression of CXCR3 splice variants in different cells (24,26). In some cells, CXCR3a supports cell proliferation (6) whereas CXCR3b delivers an antiproliferative signal.…”

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

“…[6][7][8][9][13][14][15] In CRC, it was reported that CXCR3 expression is upregulated in metastatic colon cancer cells, but not in their primary lesions, and that the CXCL10/CXCR3 axis…”

“…3 CRC cells have been found to express the chemokine receptors CXCR4 and CXCR3. [4][5][6][7][8][9] Chemokine receptor CXCR4 is the first identified chemokine receptor to play a critical role in determining the metastatic destination of breast cancer to the bone and lungs where its ligand CXCL12 is abundant. 10,11 It was also reported that metastasis of mouse colon cancer cell line CT-26 to the liver and lungs was greatly reduced when CXCR4 function was blocked.…”