Purpose: RAS mutational status in colorectal cancer (CRC) represents a predictive biomarker of response to anti-EGFR therapy, but to date it cannot be considered an appropriate biomarker of response to anti-VEGF therapy. To elucidate the function of K-Ras in promoting angiogenesis, the effect of conditioned media from KRAS mutated and wild type colon cancer cell lines on HUVECs tubule formation ability and the correspondent production of pro-angiogenic factors have been evaluated by a specific ELISA assay. Methods: Ras-activated signaling pathways were compared by western blot analysis and RTq-PCR. In addition, VEGF, IL-8, bFGF and HIF-1α expression was determined in K-RAS silenced cells. Furthermore, we conducted an observational study in a cohort of RAS mutated metastatic CRC patients, treated with first-line bevacizumab-based regimens, evaluating VEGF-A and IL-8 plasma levels at baseline, and during treatment. Results: K-RAS promotes VEGF production by cancer cell lines. At the transcriptional level, this is reflected to a K-RAS dependent HIF-1α over-expression. Moreover, the HIF-1α, VEGF and FGF expression inhibition in KRAS knocked cells confirmed these results. Within the clinical part, no statistically significant correlation has been found between progression-free survival (PFS) and VEGF-A/IL-8 levels, but we cannot exclude that these biomarkers could be further investigated as predictive or prognostic biomarkers in this setting. Conclusion: Our study confirmed the direct involvement of K-Ras in promoting angiogenesis into colon cancer cell lines.

Expression of pro-angiogenic factors as potential biomarkers in experimental models of colon cancer / Delle Monache, S.; Cortellini, A.; Parisi, A.; Pulcini, F.; Martellucci, S.; Mei, C.; Danubio, M. E.; Mattei, V.; Angelucci, A.; Ficorella, C.. - In: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY. - ISSN 0171-5216. - 146:6(2020), pp. 1427-1440. [10.1007/s00432-020-03186-x]

Expression of pro-angiogenic factors as potential biomarkers in experimental models of colon cancer

Martellucci, S.;
2020

Abstract

Purpose: RAS mutational status in colorectal cancer (CRC) represents a predictive biomarker of response to anti-EGFR therapy, but to date it cannot be considered an appropriate biomarker of response to anti-VEGF therapy. To elucidate the function of K-Ras in promoting angiogenesis, the effect of conditioned media from KRAS mutated and wild type colon cancer cell lines on HUVECs tubule formation ability and the correspondent production of pro-angiogenic factors have been evaluated by a specific ELISA assay. Methods: Ras-activated signaling pathways were compared by western blot analysis and RTq-PCR. In addition, VEGF, IL-8, bFGF and HIF-1α expression was determined in K-RAS silenced cells. Furthermore, we conducted an observational study in a cohort of RAS mutated metastatic CRC patients, treated with first-line bevacizumab-based regimens, evaluating VEGF-A and IL-8 plasma levels at baseline, and during treatment. Results: K-RAS promotes VEGF production by cancer cell lines. At the transcriptional level, this is reflected to a K-RAS dependent HIF-1α over-expression. Moreover, the HIF-1α, VEGF and FGF expression inhibition in KRAS knocked cells confirmed these results. Within the clinical part, no statistically significant correlation has been found between progression-free survival (PFS) and VEGF-A/IL-8 levels, but we cannot exclude that these biomarkers could be further investigated as predictive or prognostic biomarkers in this setting. Conclusion: Our study confirmed the direct involvement of K-Ras in promoting angiogenesis into colon cancer cell lines.
2020
angiogenic factors; colon cancer; il-8; vegf; angiogenesis inducing agents; biomarkers, tumor; cell line; tumor; colonic neoplasms; culture media; conditioned; gene silencing; genes; ras; human umbilical vein endothelial cells; humans; interleukin-8; models; biological; mutation; signal transduction; vascular endothelial growth factor a
01 Pubblicazione su rivista::01a Articolo in rivista
Expression of pro-angiogenic factors as potential biomarkers in experimental models of colon cancer / Delle Monache, S.; Cortellini, A.; Parisi, A.; Pulcini, F.; Martellucci, S.; Mei, C.; Danubio, M. E.; Mattei, V.; Angelucci, A.; Ficorella, C.. - In: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY. - ISSN 0171-5216. - 146:6(2020), pp. 1427-1440. [10.1007/s00432-020-03186-x]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1428932
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