The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts Journal Article
| Authors: | le Rolle, A. F.; Chiu, T. K.; Fara, M.; Shia, J.; Zeng, Z.; Weiser, M. R.; Paty, P. B.; Chiu, V. K. |
| Article Title: | The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts |
| Abstract: | Background: Clinical therapy for metastatic colorectal cancer (CRC) remains limited, especially when the tumor harbors a KRAS mutation. This study aimed to identify prognostic biomarkers in CRC that are accessible for therapeutic inhibition. Methods: Conditioned media from human CRC epithelial cells and myofibroblasts were screened by cytokine arrays for tumorigenic factors. The protein and mRNA expressions of these factors were determined by immunohistochemistry and gene microarrays in human CRC tissues. Prognostic biomarkers were determined by correlation of mRNA expression to overall survival in stage IV CRC patients. Inhibition of CXCL1 was performed with specific neutralizing antibody and lentiviral shRNAs. Malignant growth was assessed by soft agar growth assays and xenograft tumor growth in immunocompromised mice. Results: CXCL1 was highly secreted by KRAS mutant human CRC cells and myofibroblasts in a complementary adaptive response to serum deprivation. Elevated CXCL1 level promoted anchorage-independent growth of murine fibroblasts and human CRC cells. Inhibition of CXCL1 by neutralizing antibody and specific shRNAs decreased CRC tumor growth. Highly elevated CXCL1 expression significantly correlated with decreased overall survival in stage IV CRC patients (hazard ratio 0.28; 95% CI 0.11-0.72). Conclusions: High CXCL1 expression is a poor prognostic biomarker in metastatic CRC. CXCL1 inhibition suppressed tumorigenic growth of KRAS mutant CRC cells. © 2015 le Rolle et al. |
| Keywords: | adult; cancer survival; controlled study; human tissue; protein expression; aged; human cell; major clinical study; overall survival; nonhuman; cancer staging; prospective study; protein localization; colorectal cancer; biological marker; animal cell; mouse; disease association; gene overexpression; interleukin 8; animal experiment; animal model; tumor xenograft; gene expression regulation; cancer inhibition; chemokine; fibroblast; intestine epithelium cell; cytokine production; down regulation; upregulation; kras; oncogene k ras; myofibroblast; k ras protein; anchorage independent growth; short hairpin rna; cxcl1 chemokine; colon carcinogenesis; protein synthesis inhibition; tumor microenvironment; neutralizing antibody; cancer prognosis; human; male; female; article; cell growth assay; crc prognosis; cxcl1; cxcl1 gene |
| Journal Title: | Journal of Translational Medicine |
| Volume: | 13 |
| Issue: | 1 |
| ISSN: | 1479-5876 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2015-06-24 |
| Start Page: | 199 |
| Language: | English |
| DOI: | 10.1186/s12967-015-0555-4 |
| PROVIDER: | scopus |
| PMCID: | PMC4477596 |
| PUBMED: | 26104296 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
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