The biology and clinical implications of prostate cancer dormancy and metastasis

Abstract

Disseminated tumor cells (DTC) are detected early in the disease process in prostate cancer (PCa) patients and can persist after radical prostatectomy. DTC can remain dormant in patients with no evidence of disease for a prolonged period of time only to recur 10 or more years later. Recent advances in single cell genomics and transcriptomics have provided much needed insight into DTC biology and cancer dormancy in patients. With the development of new in vitro and preclinical models, researchers recapitulate the clinical events in patients and therefore allow further elucidation of the molecular mechanisms underlying cancer dormancy and escape. In this review we explore novel ideas on the detection, heterogeneous transcriptomic profiles, molecular and cellular mechanisms of dormancy, and potential mechanisms underlying dormancy escape by DTC. As such there is hope that identifying and targeting novel dormancy-associated pathways in patients with residual disease will have significant clinical implications for the treatment of PCa patients in the future.

Disseminated tumor cells and dormancy in prostate cancer metastasis

“…[24] For example, endothelial-derived trombospondin 1 (TSP1), bone morphogenic protein 7 (BMP7), transforming growth factor-β2 (TGF-β2) and growth arrest-specific 6 (GAS6) can mediate DTC quiescence in bone marrow. BMP7 is a TGF-β family member and is secreted by bone marrow stromal cells.…”

“…[34] CTC systems are being adapted to isolate and detect DTCs in the BM. [24] Another technique used for the detection of DTCs is the reverse transcriptase polymerase chain reaction (RT-PCR) to detect PSA. For this technique there is no enrichment required, due to high reaction sensitivity.…”

Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

“…Prostatic mesenchymal cells migrate from the primary tumor site and invade the bloodstream to metastasize to distant locations with the most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and the adrenals (13%) 23. It is tacitly assumed that these mesenchymal cells then become dormant and after a prolonged period of dormancy, which can last for decades, an unknown trigger causes the reverse transition, MET 2425. MET enables tumor growth and leads to a clinically significant metastasis.…”

The Relationship Between Dormant Cancer Cells and Their Microenvironment

“…While these models of dormancy are not mutually exclusive and might even coexist in the same patient, we will focus on cellular dormancy that is best supported by clinical evidence (Banys, Hartkopf, et al, 2012; Morrissey, Vessella, Lange, & Lam, 2015). Several studies showed that DTCs are frequently found in cancer patients with NED (Braun et al, 2005; Chery et al, 2014; Klein, 2009; Schardt et al, 2005), and the detection of DTCs in the bone marrow is associated with worse clinical outcome in many solid cancers (Braun et al, 2000; Hartkopf et al, 2014, 2015; Thorban, Rosenberg, Busch, & Roder, 2000; Wollenberg et al, 2004).…”