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Animal models for the study of metastasis

Abstract

Cancer is the second leading cause of death worldwide, preceded only by cardiovascular diseases. In this sense, studies that aim at understanding the mechanisms involved in tumor formation and metastasis process are extremely important. Cancer is a progressive disease, which has as main characteristic the uncontrolled spread of tumor cells to distant organs through a complex process known as metastasis. It is well established that cancer development and metastasis formation generally follow a course of progression through stages of increasingly aggressive and resistance to treatment, which reflects the accumulation of molecular and cellular changes. While the onset of tumor development is a reflection of a cellular proliferation, through direct activation of cell cycle machinery and signaling pathways that regulate cell cycle progression, the malignancy is a reflection of changes in the intimate relationship between the tumor cells and the host microenvironment. Therefore, animal models provide a physiologically relevant scenario for the study of the metastatic process. Attempts to model experimentally metastatic process begins with the in vitro assays designed to recapitulate the individual phases of metastatic process, such as cell migration and invasion. However, the complex nature of the metastatic process requires experimental systems more reliable to the process that occurs physiologically in vivo. In mice, several assays are used to model experimental metastasis; there are advantages and disadvantages on each. Dr. Normand Pouliot uses different cell lines of breast cancer, from clonal populations derived from a spontaneous mammary carcinoma in mice BALB/cfC3H. Among these lineages there is a derived cell which is poorly metastatic (66cl4), but form lung metastases. Dr. Normand studies, among others, the function of ²3 integrin on the metastatic process. The cell line 66cl4 is transfected with a vector containing the gene for subunit ²3 integrin (66cl4beta3). These cells express ²3 integrin and form bone metastasis. Another strain (4T1) is capable to form metastasis in multiple organs. From there, two strains with higher aggressiveness were isolated (4T1.2 and 4T1BM2). These cells metastasize even in soft tissues and bones. These last cell lines express integrins ²3 and ²4, relevant to the study of their functions during the steps of metastasis. For a better understanding of the function of integrins and stromal tumor metastasis in the laboratory of Dr. Normand has 4T1.2 cell lines and animals and 4T1BM2 knockdown for ²3 integrin. The cell line MDA-MB-231 is also used by his research group in the same animal model, but using immunocompromised mice, to verify the inhibitory function of specific proteins or natural products on metastases. All cell lines are transfected with a plasmid containing the neomycin resistance gene so that it is possible to discriminate tumor cells through the endogenous mouse assay qRT-PCR. (AU)

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