Prostate Cancer Dormancy and Reactivation in Bone Marrow

Abstract

Prostate cancer has a variable clinical course, ranging from curable local disease to lethal metastatic spread. Eradicating metastatic cells is a unique challenge that is rarely met with the available therapies. Thus, targeting prostate cancer cells in earlier disease states is a crucial window of opportunity. Interestingly, cancer cells migrate from their primary site during pre-cancerous and malignant phases to seed secondary organs. These cells, known as disseminated cancer cells (DCCs), may remain dormant for months or decades before activating to form metastases. Bone marrow, a dormancy-permissive site, is the major organ for housed DCCs and eventual metastases in prostate cancer. The dynamic interplay between DCCs and the primary tumor microenvironment (TME), as well as that between DCCs and the secondary organ niche, controls the conversion between states of dormancy and activation. Here, we discuss recent discoveries that have improved our understanding of dormancy signaling and the role of the TME in modulating the epigenetic reprogramming of DCCs. We offer potential strategies to target DCCs in prostate cancer.

Biofunctional matrix models reveal mineral-dependent mechanoregulation of bone metastatic breast cancer

“…For example, mineralizing, mature osteoblasts secrete factors (e.g. TGFβ2 or bone morphogenetic proteins 4 and 7 (BMP4/7)) that can induce tumor cell quiescence independent of matrix 82 , a possibility that should be tested with appropriate control experiments. Fluctuations in nutrient and oxygen supply or other metabolic constraints could further affect these responses.…”

Circulating tumour cells for early detection of clinically relevant cancer

“…However, cancer cell dormancy might also provide a therapeutic window of opportunity to cure cancer before the metastases are well established with many diverse subclones and a protective local ecosystem. Nevertheless, research into cancer cell dormancy is limited owing to the invasive and technically challenging nature of sample acquisition, particularly as DTCs are most commonly obtained from bone marrow 70 . Further understanding of the mechanisms underpinning cancer cell dormancy is crucial to predict metastatic potential, and Cancer Research UK and the US National Cancer Institute have jointly proposed a Cancer Grand Challenge to investigate this major issue.…”

5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling

“… 5 – 8 Importantly, genetically heterogeneous DCC populations appear to remain dormant for long periods (sometimes decades) and have the potential to reactivate as a consequence of additional genetic, chromatin remodeling, and microenvironmental changes. 9 – 11 These findings suggest that strategies that manage post-extravasation events, and thus DCC biology, may be an effective path to changing patient outcomes by preventing or significantly delaying metastatic overgrowth.…”