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.