Phenotypic evolution of cancer cells: structural requirements for survival

Abstract Enhancing the sensitivity of tumor cells to therapies has been a challenge. Major progress has been in the development of drugs specific to cancer types and new approaches for tumor targeting. But acquired tumor resistance is still eluding all attempts to prevent or overcome this phenomenon. We present information on physical constraints in the tumor microenvironment that have been associated with cancer progression and resistance to treatment and how these constraints might be mediated via mechanotransduction to the genome, hence influencing cell survival. The necessity of a careful knowledge of nuclear alterations linked with microenvironmental conditions and drug resistance phenotypes is emphasized to identify markers for the optimization of cell culture models and the measurement of the efficacy of drug treatments. The biological conditions that lead to different levels of drug sensitivity are placed in the context of drug development and delivery. Notably, in vitro three-dimensional cell culture models developed with proper materials to mimic microenvironmental constraints are likely to be superior models to readily test new drugs and drug-delivery methods. Moreover, in the future, targeted drug delivery could be designed with smart materials that adapt to microenvironmental conditions for better efficacy.