Impact of multicellular resistance on the survival of solid tumors, including micrometastases

One of the reasons for the development of cancers and their relentless malignant progression--even in the face of highly toxic anticancer therapies--is an enhanced ability to bypass mechanisms responsible for precipitating cell death. The latter include active cell death mechanisms often referred to as programmed cell death or apoptosis. Active cell death is a genetically controlled, intrinsic suicide process, and evidence is rapidly accumulating that cancers are more resistant to undergoing apoptosis than normal cells. This may be a major factor explaining the ability of small numbers of tumor cells, e.g. tumor emboli, to survive transit in the bloodstream and form distant metastases in ectopic organ sites. In addition, because many therapeutic agents ultimately kill tumor cells by inducing apoptosis, acquisition of an apoptosis-resistant phenotype could be a generic mechanism of drug or radiation resistance in cancer patients. It follows that uncovering the basis of the enhanced survival capacity of tumor cells is fundamental to gaining a better understanding of tumor progression, metastasis formation, and response to therapy. In this respect many of the principles thought to regulate apoptosis in cancers have been established using conventional, two-dimensional monolayer cell cultures of 'liquid' tumors, i.e. unicellular model systems. Suppression of apoptosis in solid tumors, however, may be governed by different cellular and genetic mechanisms. Evidence is presented in support of this hypothesis, and that multicellular architecture may render individual tumor cells within solid tumors less susceptible to apoptosis. This multicellular resistance--which may represent a form of group protection--can also be induced or acquired during cytotoxic drug chemotherapy or cytokine-mediated growth inhibition of solid tumors. It follows that disruption of solid tumor multicellularity may provide a means of enhancing the therapeutic destruction of small solid tumors such as occult micrometastases. Such disruptions may be brought about by a variety of so-called antiadhesive agents.