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.
Highlights
Besides malignant cells, solid tumors consist of numerous stromal cells, such as fibroblasts, endothelial cells, and cells of the immune system located in the tumor niche [1]
The present study focuses on the effect of interaction between colon cancer and cancer-associated fibroblast-like (CAF-like) cells in the vincristine-induced modulation of endothelial cells isolated from microvessels
To determine whether the interaction between colon cancer cells and Cancer-associated fibroblasts (CAFs) might alter the effects of vincristine treatment by modulating the cancer niche, a coculture of colon cancer and CAF-like cells (Figure 1, model 1) was prepared and treated, if necessary, with vincristine
Summary
Solid tumors consist of numerous stromal cells, such as fibroblasts, endothelial cells, and cells of the immune system located in the tumor niche [1]. Tumor progression is promoted by both the proliferation of cancer cells and their interaction with stromal cells [1,2]. The released cytokines and growth factors such as proteins from Transforming Growth Factor-beta family (TGF-βs) and interleukins remodel the components of the tumor niche to support cancer development. Cells located in the tumor niche regulate cancer progression through secreted immunomodulators, stimulating the migration and invasion capability of tumor cells [2,3]. Factors released by stromal cells might induce an alteration in other cells located in the cancer niche [2]
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