Tumour cell survival mechanisms in lethal metastatic prostate cancer differ between bone and soft tissue metastases

The complexity of survival mechanisms in cancer cells from patients remains poorly understood. To obtain a comprehensive picture of tumor cell survival in prostate cancer metastases, we interrogated 5 survival proteins that operate within 3 survival pathways in a cohort of 185 lethal metastatic prostate metastases obtained from 44 patients. The expression levels of BCL-2, BCL-XL, MCL-1, cytoplasmic Survivin, nuclear Survivin, and Stathmin were measured by immunohistochemistry in a tissue microarray. Simultaneous expression of 3 or more proteins occured in 81% of lethal prostate cancer metastasis and BCL-2, cytoplasmic Survivin and MCL-1 were co-expressed in 71% of metastatic sites. An unsupervised cluster analysis separated bone and soft tissue metastases according to patterns of survival protein expression. BCL-2, cytoplasmic Survivin and MCL-1 had significantly higher expression in bone metastases (p < 10−5), while nuclear Survivin was significantly higher in soft tissue metastases (p = 3×10−14). BCL-XL overexpression in soft tissue metastases almost reached significance (p =0.09), while stathmin expression did not (p=0.28). In addition, the expression of MCL-1 was significantly higher in AR-positive tumors. Neuroendocrine differentiation was not associated with specific survival pathways. These studies demonstrate for the first time that bone and soft tissue metastases from the same patient differ significantly in expression of a panel of survival proteins and that with regards to survival protein expression, expression is associated with metastatic site and not patient. Altogether this study suggests that optimal therapeutic inhibition may require combinations of drugs that target both bone as well as soft tissue-specific survival pathways.