Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer

Abstract

The chemokine CXCL12 has a decisive role in tumor progression by mediating pro-angiogenic and pro-metastatic effects through its receptor CXCR4. The CXCL12 pathway is connected with another chemokine, CXCL11, through its second receptor CXCR7. CXCL11 also binds to the CXCR3 receptor. CXCL11 function in tumor angiogenesis is likely receptor dependent because CXCR3 predominantly mediates angiostatic signals whereas CXCR7 mediated signaling is rather angiogenic. We therefore studied the interaction of CXCL12 and CXCL11 in an in vivo model of colorectal cancer metastasis. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice. The animals received either peritumoral application of CXCL11 or intraperitoneal injections with neutralizing antibodies against CXCL11, CXCL12 or both. Tumor growth characteristics, angiogenesis, cell migration, invasive tumor growth, tumor cell proliferation and apoptosis were studied by intravital fluorescence microscopy and immunohistochemistry during an observation period of 14 days. Local exposure to CXCL11 significantly stimulated tumor growth compared to controls and enhanced invasive growth characteristics without affecting tumor angiogenesis and tumor cell migration. Neither CXCL11 nor CXCL12-blockade had a significant impact on tumor growth and angiogenesis, whereas the combined neutralization of CXCL11 and CXCL12 almost completely abrogated tumor vessel formation. As a consequence, tumor growth and invasive growth characteristics were reduced compared to the other groups. The results of the present study underline the interaction of CXCL12 and CXCL11 during tumor angiogenesis. The combined blockade of both signaling pathways may provide an interesting anti-angiogenic approach for anti-tumor therapy.

LNA aptamer based multi-modal, Fe 3 O 4 -saturated lactoferrin (Fe 3 O 4 -bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging

“…ITAC levels were highly upregulated in treatments when compared to control. ITAC (CXCL11) is known to significantly simulate tumor growth and impart invasive characteristics to the tumor by increasing angiogenesis [66]. The q-RT-PCR studies also revealed marked upregulation in gene expression of survivin and survivin 2B.…”

MicroRNA‑144 mediates chronic inflammation and tumorigenesis in colorectal cancer progression via regulating C‑X‑C motif chemokine ligand 11

“…Not only CRC cell lines were demonstrated to release CXC-chemokines in response to cytokine stimulation, but also resected tumor explants were found to produce CXC-chemokines under stimulation, even in cases with initially low CXC-levels (26). Among these CXC-chemokines, CXCL11 is deemed to be an important factor during colonic tumorigenesis (5,28). Similar to the results of microarray data analysis, we found that the expression levels of CXCL11 were significantly upregulated in excised tumor specimens compared with normal tissues.…”

“…C-X-C motif chemokine ligand 11 (CXCL11), released by immune cells during inflammation, is a small cytokine that may contribute to progression of colonic tumorigenesis (5). CXCL11 may regulate the chemotaxis of cells through interaction with a subset of 7-transmembrane, G protein-coupled receptors (6).…”

C-X-C motif receptor 7 in gastrointestinal cancer

“…Previous studies have demonstrated that CXCR7 is differentially expressed in colorectal cancer at the transcriptional and protein levels, as well as in the cell membrane (38)(39)(40)(41)(42)(43). CXCR7 expression increased following lipopolysaccharide treatment in the SW480 and COLO 205 colorectal carcinoma cell lines, which express Toll-like receptor 4 (TLR4)/myeloid differential protein-2.…”