Drug resistance and the microenvironment: nature and nurture
Introduction
Research into targeted cancer therapy against specific molecules or pathways is being aggressively pursued and shows great promise. Nevertheless, the vast majority of cancers are still treated with conventional cytotoxic drugs. These drugs are used with variable success depending on the cancer type and the stage of disease, but drug resistance remains a major obstacle to the successful use of these agents. Both intrinsic resistance, where the tumor cells are resistant at the time of initial treatment, and acquired resistance, which develops during treatment because of the selection for drug-resistant cells in the tumor, are observed (Gottesman, 2002). While acquired chemoresistance is more amenable to experimental scrutiny, several studies have also examined the mechanisms of intrinsic drug resistance. It is anticipated that there will be extensive overlap between the mechanisms present in these two distinct manifestations of drug resistance.
Although much of the research into cancer drug resistance has initially focused on the malignant cells, it has now become clear that host factors can significantly affect the success of chemotherapy. For example, immunomodulation, the pharmacological clearance of drug by the liver, and poor tolerance to the side effects can all affect the outcome of therapy (Gottesman, 2002). Interestingly, the tumor microenvironment can also influence the resistance of cancer cells to chemotherapy. What are the underlying mechanisms? For the purpose of this review, the mechanisms of microenvironment-induced drug resistance can be grouped into two main categories: (a) mechanisms that lead to reduced damage/inhibition of the primary target (e.g. changes in rates of drug entry or exit from the cells), and (b) mechanisms that lead to increased tolerance to the damage (e.g. decreased sensitivity to apoptosis). As an example of the first type of mechanisms, the extracellular matrix (ECM) can affect tumor cell survival by preventing the penetration of the drug into the tumor (Jain, 1998, Tannock et al., 2002). In addition the microenvironment can affect the sensitivity of the tumor cells to apoptosis (Dalton, 1999, St. Croix and Kerbel, 1997, St. Croix et al., 1996b). Interactions of cancer cells with each other (cell–cell adhesion), with various growth factors, and with components of the ECM can drastically affect the apoptosis sensitivity of these cells and the response to chemotherapeutic drugs. The multidrug resistance phenotype that results from direct cell contact with the environment has been coined “cell adhesion-mediated drug resistance,” or CAM-DR (Dalton, 1999). This review will focus on recent advances regarding CAM-DR, and how the tumor cells may actively reorganize their microenvironment to increase cell adhesion and drug resistance.
Section snippets
Cell–cell adhesion influences drug resistance
The influence of the environment on tumor cell survival in the presence of cytotoxic agents was noted over 30 years ago, when it was observed that multicellular spheroids of tumor cells were more resistant to anticancer agents than the corresponding monolayer cultures, and that these differences were not due to a compromised ability of the drug to penetrate the spheroids (Durand and Sutherland, 1972). Similar findings have been reported in many different experimental systems (dit Faute et al.,
Growth factors and drug resistance
The influence of growth factors on tumor drug resistance was first observed in myeloma cells. IL-6, a cytokine secreted by bone marrow stromal cells, is known to regulate survival and proliferation of myeloma cells (Klein et al., 1995). Interestingly, IL-6 can increase resistance of myeloma to various chemotherapeutic drugs, by preventing apoptosis (Chauhan et al., 1997, Lichtenstein et al., 1995). Activation of the IL-6 receptor is believed to lead to downstream signaling through the JAK/STAT
The ECM in drug resistance
The ECM, a complex assembly of collagen, proteoglycans and other molecules, is an important constituent of normal tissues and provides essential cues for cell development, migration, adhesion, proliferation, survival, and other metabolic functions (Stupack and Cheresh, 2002). Tumor cells are surrounded by ECM produced by neighboring stromal cells and ECM components can interact with tumor cell integrins and affect their behavior, including their sensitivity to chemotherapeutic drugs (Hoyt et
A model for ECM-induced drug resistance
Collectively, the studies described above demonstrate that the ECM can influence drug resistance in vivo. Interestingly, it has been suggested that the tumor cells may condition the neighboring stroma in order to induce the production of protective ECM proteins (Rintoul and Sethi, 2002). Various cytokines and growth factors produced by the tumor might be responsible for this effect. In addition, since tumor cells are known to produce ECM components, it is tempting to speculate that tumor cells
Perspectives
The suggestion that tumor cells may actively reorganize their environment raises many interesting issues. First, how can tumor cells expressing favorable ECM-modulating proteins be selected during chemotherapy? It is clear that these interaction are favorable to tumor cell survival, even in the absence of drugs, so a fraction of the tumors may already express these proteins even in the absence of the selective pressure imposed by the drug, explaining intrinsic drug resistance. However, in
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