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Colorectal cancer (CRC) affects more than one million people worldwide each year. For metastatic CRC, the effectiveness of this type of treatment is limited. Indeed, mortality is difficult to reduce drastically because there are still many therapeutic failures explained in particular by the development of chemoresistance or the presence of cancer cells with aggressive characteristics. We show that the acquisition of chemoresistance confers first of all a greater migratory and invasive power. We also show that two of the chemoresistant lines, HCT-116/5FU and HCT-116/OXA acquire the ability to form their own vascular network, which is called vascular mimicry. We therefore sought to understand which actor could be responsible for the observed changes. We finally show that VEGF-A is secreted in greater abundance in chemoresistant cells. We confirm this with the use of a clinically approved anti-VEGF inhibitor in the treatment of CCR, aflibercept. Indeed, we show that aflibercept is capable of significantly reducing the migratory, invasive potential of chemoresistant tumor cells. It also significantly reduces the phenomenon of vascular mimicry. Thus, we show very clearly the implication of VEGF signaling in the development of this "aggressive" phenotype following the acquisition of chemoresistance. We even offer a partial therapeutic option, aflibercept., Le cancer colorectal (CCR) touche chaque année plus d’un million de personnes dans le monde. Dans le cas des CCR métastatiques, l’efficacité de ce type de traitement est limitée. En effet, la mortalité peine à diminuer drastiquement car il existe encore de nombreux échecs thérapeutiques expliqués notamment soit par le développement d’une chimiorésistance, soit la présence de cellules cancéreuses présentant des caractéristiques agressives. Nous montrons que l’acquisition d’une chimiorésistance confère tout d’abord un pouvoir migratif et invasif plus importants. Nous montrons également que deux des lignées chimiorésistantes, les HCT-116/5FU et les HCT-116/OXA acquièrent la capacité à former leur propre réseau vasculaire, c’est ce que l’on appelle le mimétisme vasculaire. Nous avons donc cherché à comprendre quel acteur pouvait être responsable des modifications observées. Nous montrons finalement que le VEGF-A est sécrété de manière plus abondante dans les cellules chimiorésistantes. Nous confirmons cela par l’utilisation d’un inhibiteur anti-VEGF approuvé cliniquement dans le traitement du CCR, l’aflibercept. En effet, nous montrons que ce dernier est capable de réduire de manière significative le potentiel migratif, invasif des cellules tumorales chimiorésistantes. Il réduit aussi considérablement le phénomène de mimétisme vasculaire. Ainsi, nous montrons très clairement l’implication de la signalisation VEGF dans le développement de ce phénotype « agressif » suite à l’acquisition d’une chimiorésistance. Nous offrons même une option thérapeutique partielle, l’aflibercept.

Introduction. Cancer mortality is principally associated with the presence of drug-resistant, invasive subpopulations of tumor cells. However, the functional and mechanistic interactions between the two phenotypes are incompletely understood. Colorectal cancer (CRC) cells produce the vast majority of VEGF in the cancer environment and display endogenous VEGFR1/VEGF signaling which is believed to promoted survival under stress. Methods. Migration and invasion was determined by the transwell assay (Boyden Chamber). For the tube formation assay, CRC cells were seeded onto 3D matrigels and incubated at 37° for 24 hr monitored by videomicroscopy. Determination of VEGF ligands was carried out by ELISA. Results. We here characterize a panel of 4 isogenic CRC cell lines comprised of the parental HCT-116 cells and three independently derived sublines resistant to 5-fluorouracil, oxaliplatin and SN-38. Resistant cells secreted 3-7 fold more VEGF, while the HCT-116/5-FU cells also secreted 2 times more PlGF, compared to the parental cells. VEGF signaling is known to promote CRC cell migration and invasion. In agreement, resistant cells showed 6-11 fold increased migration, whereas the invasive capacity had increased 6-15 fold. Aflibercept inhibits all three VEGFR1 ligands (VEGF-A, VEGF-B and PlGF) on CRC cells accordingly, addition of aflibercept resulted in a significant decrease in both migration and invasion. Two of the three resistant cell lines were able to do vascular/vasculogenic mimicry by forming capillary-like cellular networks which could be significantly attenuated by aflibercept. Conclusions.Taken together, our results indicate that acquired resistance to genotoxic agents may be accompanied by an increased invasive potential mediated, in part, by VEGF signaling that can be attenuated by aflibercept. Disclosures No relevant conflicts of interest to declare.