SDF-1/CXCR4 axis promotes directional migration of colorectal cancer cells through upregulation of integrin αvβ6

Abstract

Colorectal cancer (CRC) displays a predilection for metastasis to liver. Although stromal cell-derived factor-1 (SDF-1)/CXCR4 plays an important role in the liver metastasis, the molecular mechanism still remains obscure. We previously reported that integrin αvβ6 was implicated in the progression of CRC. However, no data are currently available on the cross talk between CXCR4 and αvβ6. In the present study, we first demonstrated the cross talk between CXCR4 and αvβ6 and their role in liver metastasis of CRC. We analyzed 159 human CRC samples and found that expression of CXCR4 and αvβ6 was significantly associated with liver metastasis, and interestingly expression of αvβ6 significantly correlated with expression of CXCR4. Both CXCR4 and αvβ6 were highly expressed in metastatic CRC cell lines HT-29 and WiDr, whereas both of them were exiguous in non-metastatic cell line Caco-2. Furthermore, inhibition of αvβ6 significantly decreased SDF-1α-induced cell migration in vitro. SDF-1/CXCR4 could upregulate αvβ6 expression through phosphorylation of ERK and activation of Ets-1 transcription factor. In conclusion, we demonstrate that SDF-1/CXCR4 induces directional migration and liver metastasis of CRC cells by upregulating αvβ6 through ERK/Ets-1 pathway. These data support combined inhibition of CXCR4 and αvβ6 to prevent development of liver metastasis of CRC.

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…In ovarian cancer, SDF-1 has recently been shown to upregulate the Integrin molecules ß1 and ß3 and to promote invasion by the SDF-1-specific C-X-C chemokine receptor type 4 (CXCR4) axis [162]. In colorectal cancer, αvß6 Integrin was shown to effect the same kind of upregulation [163]. These findings may be of clinical relevance, as CXCR4, often expressed and detected in cancers, is found only at low or non-detectable levels in healthy tissues [164].…”

Co-expression of CXCR4 and CD133 in gastric neoplastic tissue and their correlation with clinicopathological factors and prognosis in gastric cancer

“…1 Stromal cell-derived factor (SDF)-1α is cognate ligand of CXCR4 and high levels expression of SDF1α /CXCR4 axis is associated with lung, liver and lymph nodes metastasis. 2 SDF1α /CXCR4 axis plays key role in human development, including organogenesis, vascularisation, haematopoiesis, and embryogenesis. 3 More recent evidence shows that the SDF-1α /CXCR4 axis acts as key regulator of metastasis in leukemia & several solid tumors and also plays an important role in self renewal, differentiation potential, cell adhesion, tumorigenicity & tumor vascularization capacity of tumor cell.…”

LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells

“…28 In order to detect the influence of LPS to SDF-1a/CXCR4 axis, the expression of SDF-1a and CXCR4 was determined. We found that SDF-1a expression was significantly increased in the liver of LPSchallenged BABL/c mice ( Fig.…”