Disseminated tumor cells and dormancy in prostate cancer metastasis

Abstract

It has been reported that disseminated tumor cells (DTCs) can be found in the majority of prostate cancer (PCa) patients, even at the time of primary treatment with no clinical evidence of metastatic disease. This suggests that these cells escaped the primary tumor early in the disease and exist in a dormant state in distant organs until they develop in some patients as overt metastases. Understanding the mechanisms by which cancer cells exit the primary tumor, survive the circulation, settle in a distant organ, and exist in a quiescent state is critical to understanding tumorigenesis, developing new prognostic assays, and designing new therapeutic modalities to prevent and treat clinical metastases.

The Cohesive Metastasis Phenotype in Human Prostate Cancer

“…Prostate cancer metastasizes early to pelvic lymph nodes and, as distinct from other epithelial cancers, predominantly metastasizes to bone [21–23]. Metastases in the lymph node, vessels and bone are observed as clusters (Fig.…”

“…2). When these cohesive-clusters have been studied, they contain no mitotic figures and are Ki-67-negative, both in breast cancer CTCs [25] and in prostate cancer metastases [21,23]. These findings suggest that single CTCs may not be the primary origin of metastatic tumors but, rather, that cohesive CTC-clusters, which have been identified as more efficient than individual CTCs in seeding distant metastases [26,27] (reviewed in [3]), should be a primary therapeutic target.…”

“…There is a compelling clinical need to include the testing of anti-metastatic therapies, along with systemic chemotherapy approaches, for epithelial cancer treatment [21]. An alternative strategy also is required to tailor therapies to prostate cancer that requires aggressive treatment—avoiding both expensive and high-morbidity approaches when possible [20].…”

Identification and Phenotypic Plasticity of Metastatic Cells in a Mouse Model of Melanoma

“…Metastatic tumor cells in circulation have been long recognized, and CTCs in the blood stream have been successfully isolated from human blood [59][60][61]. An FDA approved detection system, Cellsearch, is available for the isolation of CTCs and has been successfully used for monitoring patients with metastatic breast, prostate and colon cancers [62]. Nonetheless, no consensus has been reached regarding melanoma CTCs because of sample scarcity, cohort heterogeneity, and the application of Cellsearch on melanoma patients seems not sensitive enough and needs further investigations [63].…”

“…In addition to these Zn-finger transcription factors, ectopic expression of bHLH family transcription factor Twist1 resulted in the loss of E-cadherin mediated cell-cell adhesion, expression of mesenchymal markers and induction of cell motility, hallmarks of EMT in normal mammalian cells. Suppression of Twist in highly metastatic mammary carcinoma cells inhibited their metastatic capacity from the mammary gland to the lung in a murine breast tumor model [62]. Correlations between Twist1 and Snail2 during EMT in cancer metastasis were also discussed [63].…”