The tumour microenvironment is believed to be involved in development, growth,
metastasis, and
therapy resistance of many
cancers. Here we show
survivin, a member of the
inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in
cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type
survivin (Surv-WT) or the previously described dominant-negative mutant
survivin (Surv-T34A), which has proven pro-apoptotic effects in
cancer cells but not in normal proliferating cells.
Cancer cells grown in
conditioned medium (CM) taken from Surv-WT cells absorbed
survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that
survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting
survivin's function in tumourigenesis. Alternatively,
cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for
survivin in the control of
cancer aggressiveness and spread, and should result in the genesis of additional
cancer treatment modalities.