Abstract
BackgroundThe cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs. 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.MethodsTo 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. These parameters were evaluated at non toxic concentrations which did not affect HT1080 cell proliferation.ResultsWe 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. 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.ConclusionThis 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. 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.
Highlights
The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs
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)
Determination of doxorubicin subtoxic concentrations in 3D cultures To rule out a putative direct cytotoxic impact of the drug on cell migration, the ability of doxorubicin to decrease tumor cell motility was investigated at concentrations exhibiting no or limited effect on tumor cell proliferation
Summary
The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs. 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) 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. It is of primary importance in the search of cell invasion inhibitors to consider the tumor cell microenvironment in in vitro drug screening regimens 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 [9]. In vivo, such environmental causes have been suspected to contribute to cancer cell survival after initial therapy, allowing resistant cells to proliferate
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