Cytoskeleton Reorganization in EndMT-The Role in Cancer and Fibrotic Diseases.

Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial-mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that acquire a mesenchymal phenotype. EndMT-derived cells, known as the myofibroblasts or cancer-associated fibroblasts (CAFs), are characterized by the loss of cell-cell junctions, loss of endothelial markers, and gain in mesenchymal ones. As a result, the endothelium ceases its primary ability to maintain patent and functional capillaries and induce new blood vessels. At the same time, it acquires the migration and invasion potential typical of mesenchymal cells. The observed modulation of cell shape, increasedcell movement, and invasion abilities are connected with cytoskeleton reorganization. This paper focuses on the review of current knowledge about the molecular pathways involved in the modulation of each cytoskeleton element (microfilaments, microtubule, and intermediate filaments) during EndMT and their role as the potential targets for cancer and fibrosis treatment.

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

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-ßs 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 ß-tubulin composition. While higher levels of tubulin-ß2 and tubulin-ß4 caused slowed polymerization and reduced the level of factors secreted to the extracellular matrix, tubulin-ß3 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.

Invasive Colon Cancer Cells Induce Transdifferentiation of Endothelium to Cancer-Associated Fibroblasts through Microtubules Enriched in Tubulin-ß3.

Colon cancer, the second leading cause of cancer-related deaths in the world, is usually diagnosed in invasive stages. The interactions between cancer cells and cells located in their niche remain the crucial mechanism inducing tumor metastasis. The most important among those cells are cancer-associated fibroblasts (CAFs), the heterogeneous group of myofibroblasts transdifferentiated from numerous cells of different origin, including endothelium. The endothelial-to-mesenchymal transition (EndMT) is associated with modulation of cellular morphology, polarization and migration ability as a result of microtubule cytoskeleton reorganization. Here we reveal, for the first time, that invasive colon cancer cells regulate EndMT of endothelium via tubulin-ß3 upregulation and its phosphorylation. Thus, we concluded that therapies based on inhibition of tubulin-ß3 expression or phosphorylation, or blocking tubulin-ß3's recruitment to the microtubules, together with anti-inflammatory chemotherapeutics, are promising means to treat advanced stages of colon cancer.

[Modern methods in analysis of microtubules dynamic in vivo]. / Nowoczesne metody przyzyciowej analizy polimeryzacji mikrotubul.

Microtubules are involved in any vital cellular activities, including the maintenance of cell shape, division, migration and intracellular transport. Microtubule dynamics is regulated by the balance between their polymerization and depolymerization. Microtubule stability is dependent on their alpha and beta subunits composition, tubulin post-translational modifications and interaction of microtubules with microtubule-associated proteins (MAPs). Disruption of these processes can lead to a number of pathological conditions such as cancer, cardiovascular disease, or the fibrosis development. This review summarizes the current knowledge of the modern methods of microtubule polymerization analysis. This allows a better understanding of the structure and mechanisms played by microtubules in their physiological functions and the development of pathological conditions resulting from their disorder.