Indeed, it has been demonstrated as a key determinant of cell response to anticancer drugs this, being due to multiple mechanisms including limited drug penetration, tumor cell adaptation to hypoxia, presence of an acidic extracellular pH and direct contact between cancer cells and the extracellular matrix or adjacent cells that induce cell-mediated adhesion resistance. For this reason, it is of primary importance in the search of cell invasion inhibitors to consider the tumor cell microenvironment in in vitro drug screening regimens. One of the limitations of such studies is that they were performed on conventional tissue culture substrate, a situation that does not take into account the tumor cell microenvironment in which tumor cells in vivo exert complex interactions with their immediate neighbors and the extracellular matrix (ECM). The underlying mechanism deals with either downregulation of matrix metalloproteinases or disorganization of cytoskeleton and focal contacts. Indeed, doxorubicin and related compounds such as aclacinomycin, or DA-125, a doxorubicin analogue, have been shown to inhibit in vitro invasion of various tumor cell lines originating from solid tumors when used at low concentrations. In the search of antitumor agents with anti-invasive properties, evidence has recently accumulated indicating that anthracyclines, one of the most potent classes of chemotherapeutic agents in clinical use, inhibit tumor cell invasion.
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Given the fact that most current chemotherapeutic protocols aim at direct inhibition of tumor cell growth, the development of antimetastatic agents could be an effective means to prevent colonization, thereby enabling the containment of primary tumors in a chemically manageable form.
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In fact, it is generally considered that 90% of human cancer deaths can be attributed to local invasion and/or distant metastases. This process confers poor prognosis for the affected patient. Consistent with the previously shown resistance to the cytotoxic effect in a 3D context, our results highlight the importance of the matrix configuration on the tumor cell response to antiinvasive drugs.Ĭancer metastases are particularly challenging for the medical field and represent a major hurdle in cancer chemotherapy of solid neoplasia. This study suggests the lack of antiinvasive effect of doxorubicin in a 3D environment which is generally considered to better mimic the phenotypic behaviour of cells in vivo. Regarding the impact of doxorubicin on the focal adhesion complexes, unlike in 2D systems, the data indicated that the drug neither affected β1 integrin expression nor the state of phosphorylation of FAK and RhoA. We show that while doxorubicin decreased cell migration properties by 70% in conventional two-dimensional (2D) culture, this effect was completely abolished in a 3D one. These parameters were evaluated at non toxic concentrations which did not affect HT1080 cell proliferation. To this purpose, we studied the migratory parameters, the integrin expression, and the activation state of focal adhesion kinase (FAK) and GTPase RhoA involved in the formation of focal adhesions and cell movement. The present study was designed to investigate whether this microenvironment can influence the antimigratory effect of an anthracycline drug, doxorubicin, when tumor cells are grown in a matrix of type I collagen, a three-dimensional (3D) context which simulates a natural microenvironment.
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The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs.