The tumor microenvironment is a dominant force in multidrug resistance

Abstract

The emergence of clinical drug resistance is still one of the most challenging factors in cancer treatment effectiveness. Until more recently, the assumption has been that random genetic lesions are sufficient to explain the progression of malignancy and escape from chemotherapy. Here we propose an additional perspective, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context. Targeting this dynamic interplay could be considered a new avenue to prevent therapeutic resistance, and may even provide a promising effective cancer treatment.

Fig. 1

Polarized mammary structures are resistant to apoptosis induced by chemotherapeutics. When cultured on 2D monolayer, both non-malignant (A) and malignant (B) human breast cells show a similar rate of apoptosis upon treatment with distinct immunomodulators and chemical agents. However, when placed in 3D lrECM, S-1 non-malignant cells form polarized growth-arrested acini resistant to drug cytotoxic effects (C), whereas T4-2 malignant cells appear highly disorganized, proliferative and sensitive to therapeutic drugs (D). Perturbing apical–basal polarity of S-1 acini, by treatment with E-cadherin function-blocking antibody, results in a dramatic increase of sensitivity to drug agents (E). Conversely, restoring cell and tissue polarity in T4-2 structures, by treatment with β1 integrin inhibitory antibody, induces malignant cells to ‘revert’ and provides them resistance to chemotherapeutic agents (F). Polarized mammary epithelial cells are resistant to apoptosis induced by cytotoxic agents, either growth-arrested (C) or proliferating (G). In contrast, growth-arrested but reversely polarized S-1 cells grown in collagen I ECM undergo apoptosis (H, upper panel); once exposed to lrECM, these S-1 non-polar structures polarize and become resistant to apoptosis (H, lower panel).

Fig. 2

Mammary gland tissue becomes increasingly stiffer during tumor progression. Each tissue has a particular ‘stiffness phenotype’ (stiffness measured in Pascals – Pa) and each cell type is finely tuned to the specific tissue in which it resides. For example, fat tissue is much softer than cartilage. Thus, a highly compliant matrix favors adipogenesis, whereas osteoblast differentiation is optimal on stiffer ECM. Similarly, normal mammary gland development is optimally supported by interaction of epithelial cells with a soft matrix. During tumor progression, breast tissue becomes increasingly stiffer and tumor cells become significantly more contractile and hyper-responsive to highly compliance signals. Although breast tumors are much stiffer than the normal mammary gland, the material properties of a breast tumor or any other physiological environment remain significantly softer than those of glass or plastic culture dishes.

Fig. 3

Postulated steps in drug resistance and dormancy. Cancer cells exist in intimate relationship with other cells within the tumor and the surrounding microenvironment. This dynamic coalition ensures tumor survival and proliferation, but may determine also the overall sensitivity to anti-cancer drugs. The selective pressure imposed by conventional chemotherapy regimes eliminates certain cells within the tumor population. The surviving population following chemotherapy is referred to as minimal residual disease; despite the malignant genome, these cells can find a microenvironment to allow them to remain polar, blend into an organized context and survive therapeutic insults. These protective microenvironments facilitate the development of drug resistance by distinct molecular mechanisms, including: intercellular and cell-ECM adhesion; cell communication by various soluble factors and overproduction of proteolytic enzymes; alterations in mechanosensing that disrupt tensional homeostasis in the tissue; phenotypic transitions for cells to become isolated, motile and resistant to apoptosis; and a state of protective quiescence, either within the tumor or in specific organs depending on the origin of the primary tumor. Over time, drug resistant cells develop even more permanent mechanisms of resistance (acquired resistance), and eventually cause disease recurrence and metastatic growth.