Nonsteroidal Anti-Inflammatory Drugs Prevent Vincristine-Dependent Cancer-Associated Fibroblasts Formation

Abstract

Vincristine is used in the clinical treatment of colon cancer, especially in patients diagnosed in the advanced phase of cancer development. Unfortunately, similar to other agents used during antitumor therapy, vincristine might induce chemoresistance. Studies of this process focus mainly on the analysis of the molecular mechanisms within cancer, usually ignoring the role of stromal cells. Our present findings confirm that vincristine stimulates the secretion of tumor growth factors class beta and interleukin-6 from cancer-associated fibroblasts as a result of paracrine stimulation by cancer cells. Based on alterations in morphology, modulation of capillary formation, and changes in endothelial and mesenchymal marker profile, our findings demonstrate that higher levels of tumor growth factor-βs and interleukin-6 enhance cancer-associated fibroblast-like cell formation through endothelial–mesenchymal transition and that nonsteroidal anti-inflammatory drug treatment (aspirin and ibuprofen) is able to inhibit this phenomenon. The process appears to be regulated by the rate of microtubule polymerization, depending on β-tubulin composition. While higher levels of tubulin-β2 and tubulin-β4 caused slowed polymerization and reduced the level of factors secreted to the extracellular matrix, tubulin-β3 induced the opposite effect. We conclude that nonsteroidal anti-inflammatory drugs should be considered for use during vincristine monotherapy in the treatment of patients diagnosed with colorectal cancer.

The New Model of Snail Expression Regulation: The Role of MRTFs in Fast and Slow Endothelial–Mesenchymal Transition

“…Cell morphology was analyzed using a microscope (Olympus, Olympus Optical Co., Ltd., Tokyo, Japan) and the representative images were captured using an Olympus digital camera. Next, the changes in cell morphology were estimated by measuring the elongation ratio (the ratio of the longer to the shorter axis) of the analyzed cells using Meta ® Morph [ 51 ].…”

TUBB4B Downregulation Is Critical for Increasing Migration of Metastatic Colon Cancer Cells

“…Microtubules fraction was isolated from the cells as described previously [26]. Briefly, cell pellets were homogenized in PB buffer (0.1 M K-PIPES (pH 6.8), 0.5 mM MgCl 2 , 2 mM EGTA, 0.1 mM EDTA, 0.1% ( v / v ) β-mercaptoethanol, 1 mM ATP with PhosStop phosphatase inhibitor and cOmplete Protease Inhibitor Cocktail) and centrifuged (100,000× g ; 60 min; 4 °C).…”

The Role of Interleukins in Colorectal Cancer

“…Recent studies on IL-6 have mainly focused on the EMT, metastasis and TME, which contributes to the treatment of CRC. For example, nonsteroidal anti-inflammatory drugs and metformin were used to inhibit IL-6-mediated EMT in CRC, showing a good result in CRC regression 84 - 86 . As an interleukin which has been thoroughly researched in a long time, IL-6 deserves more attention to drug tests and clinical treatment.…”