Drug resistance and the microenvironment: nature and nurture

Abstract

Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have an important impact on the success of chemotherapy. Indeed, cell–cell and cell–matrix interactions can influence the cancer cells sensitivity to apoptosis and affect drug resistance. A model is proposed in which the tumor cells may actively reorganize their environment to maximize their survival in the presence of anticancer agents.

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.