MESENCHYMAL FEATURES MEDIATED BY TWIST1 IN COLORECTAL CANCER CELLS AND MICROENVIRONMENT
Tesi di Dottorato
Data di Pubblicazione:
2011
Citazione:
MESENCHYMAL FEATURES MEDIATED BY TWIST1 IN COLORECTAL CANCER CELLS AND MICROENVIRONMENT / G. Celesti ; tutore: Massimo Roncalli ; correlatore: Luigi Laghi. Universita' degli Studi di Milano, 2011 Jun 06. 23. ciclo, Anno Accademico 2010. [10.13130/celesti-giuseppe_phd2011-06-06].
Abstract:
Background. Colorectal cancer (CRC) is a major cause of death for cancer in western countries, ranking third in both sexes. Therapeutic developments in the past decades have extended life expectancy in patients with advanced disease (i.e., stage III), and even for those with distant metastasis (i.e., stage IV). Most treatments for advanced disease nowadays include a combination of chemotherapy with target therapy. Despite advances, the fact that metastatic colorectal cancer remains largely incurable, pushes to pursue a better understanding of the factors underlying cancer progression. Nowadays, a major field of investigation is the relationship between epithelial tumor cells and the surrounding compartment, namely tumor microenvironment, and in particular its contribution to cancer progression.
The tumor microenvironment essentially comprises tumor infiltrating cells, vasculature, extracellular matrix, plus other matrix associated molecules. Transformed cells can modulate the functions of stromal cells, likely to facilitate their own growth and survival. In this Darwinian perspective, outgrowth of cancer cells goes together with local changes. Such changes, like clonal ones, are likely progressive, from the stage of local invasion, up to regional lymph-node colonization and finally to the development of distant metastasis.
Infiltrating cells are a mix of populations having myeloid or mesenchymal origin, including tumor-associated macrophages, myeloid -derived suppressor cells, mast cells, monocytes, neutrophils, CD3+ T cells, natural killers, dendritic cells, endothelial cells, mesenchymal stem cells and cancer-associated fibroblasts. Taken together, all these players are involved in a double-faced game, in which an anti-tumor effect (such as that exerted by CD3+ cells in early CRC, [1]) is counteracted by a cancer promoting one (e.g., that exerted by macrophages [2]. Currently, this cancer-microenvironment match implies contradictory and controversial data, largely depending upon the investigated cell population and upon the experimental setting. This Ariadnes' thread seems unravelled, mainly because of the contemporaneous evolution of both tumor and microenvironment cells during multi-stage tumor progression. What is certainly perceived today, is that a switch from a genetic to a non-clonal prospective is required to understand tumor evolution. Clearly, the dynamic architecture of the stromal compartment and the interactions therein, need to be reconciled with the evidences concerning genetic irreversible changes in stromal cells. The latter include loss of heterozygosis, microsatellite instability (MSI) [3], trisomy of Chromosome 7 in connective tissues elements of CRC [4], and p53 mutations (in the stroma of breast carcinoma[5]). These surprising results rise the possibility that the stromal compartment contains not only an admixture of non-neoplastic cells, but also cancer cells with an aggressive and invasive phenotype which became able to invade the surrounding tissues by mimicking fibroblast morphology. This metamorphosis would be possible through the re-use of an embryonic program by cancer cells, that is the epithelial to mesenchymal transition (EMT). Originally, in a murine model of spontaneous metastatic breast cancer, Weinberg and Coll. demonstrated that the highest aggressive potential of cancer cell was reached after their transition from an epithelial to a mesenchymal morphology (i.e., EMT), driven by Twist1 gene [6]. Twist1 expression and EMT are strictly associated with the acquisition of a spindle-like fibroblast morphology, the down-regulation of the epithelial marker E-cadherin and the expression of mesenchymal ones (N-cadherin and vimentin), with metastases development, and with the inhibition of the key
Tipologia IRIS:
Tesi di dottorato
Keywords:
epithelial to mesenchymal transition ; colorectal cancer ; metastasis ; twist1
Elenco autori:
G. Celesti
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