Disseminated Tumor Cells and Dormancy
Evidence suggests that tumor cells disseminated from the prostate localize to the bone marrow niche, displace HSCs, and either proliferate to form a metastatic mass or enter a state of dormancy.93 Dissemination from the primary site to reside in distant environments is an early event seen in prostate cancer, as patients who undergo prostatectomy may present with metastases many years later.94,95
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Disseminated tumor cells (DTCs) reside in the bone marrow niche where they can remain dormant and resistant to chemotherapy for long periods of time (>10 years) before emerging to form metastatic outgrowths.94 Although most patients with prostate cancer harbor DTCs, not all will develop metastases, suggesting that mechanisms exist to maintain DTC dormancy as well as to promote awakening.95
Several bone marrow–dependent mechanisms have been identified as modulators of prostate cancer DTC dormancy.
In the endosteal niche, the osteoblast expression of Anxa2 combined with the expression of the Anxa2 receptor (Anxa2R) by HSCs is important in regulating HSC homing to the niche. Anxa2R expression is elevated in metastatic prostate tumor cells and, as such, the Anxa2/Anxa2R axis can be hijacked to promote the homing of prostate tumor cells to the niche.
Interrupting the interaction between Anxa2 and Anxa2R is sufficient to reduce tumor burden in the niche.96 Evidence has revealed that the ligation of Anxa2 with Anxa2R stimulates the expression of the Axl receptor tyrosine kinase.97 Axl, along with Tyro3 and Mer, are receptors for osteoblast-expressed growth arrest-specific 6 (GAS6).98
As was the case with Anxa2/Anxa2R, the GAS6/Axl interaction typically occurs between HSCs and osteoblasts and is one mechanism of controlling HSC dormancy.98
Engaging osteoblast-expressed GAS6 and tumor cell–expressed Axl yields a similar result that includes growth arrest and enhanced drug resistance in prostate cancer cells.97 Following-up on these observations, data show that these activities may be specific to the Axl receptor compared with other GAS6 receptors.98
A high ratio of Axl to Tyro3 expression encourages maintenance of a dormant state, whereas reducing the expression of Axl and increasing the expression of Tyro3 has been shown to promote outgrowth.98
Interactions between osteoblasts and tumor cells may be important to DTC dormancy. Prostate cancer cells that bind with osteoblasts also upregulate the expression of TANK-binding kinase 1 (TBK1). In vitro and in vivo knockdown of TBK1 resulted in decreased drug resistance, suggesting that TBK1 may also play a role in dormancy and drug resistance.100
A high p38:ERK ratio has been shown to maintain dormancy of squamous carcinoma cells, whereas interactions with the microenvironment can stimulate a switch to high ERK:p38 and reverse dormancy.101
Bone marrow–derived transforming growth factor (TGF) β2 has been implicated in maintaining the dormancy of DTCs by p38 activation, and inhibiting either the TGF-β receptor 1 or p38 leads to the proliferation and metastasis of DTCs.102 Similarly, bone morphogenetic protein 7 triggers prostate cancer DTC dormancy in part by activating p38.103
Although much focus has been on the endosteal niche, the vascular niche also has implications for DTC dormancy. Through the use of advanced imaging techniques, dormant DTCs have been shown to home to perivascular niches in the bone marrow and the lungs.104
These niches promote dormancy through the expression of TSP-1; however, dormancy is lost in regions of sprouting vasculature due to a loss of TSP-1 and the activation of TGF-β and periostin.104
In vivo experiments in mice receiving bone marrow transplantation revealed that fewer HSCs successfully engraft in tumor-bearing mice, suggesting that the tumor cells occupying the niche outcompete HSCs for residence.105
In addition, expanding the endosteal osteoblast niche with parathyroid hormone (PTH) promoted metastasis, whereas decreasing the size of the niche using conditional osteoblast knockout models reduced dissemination.105
Tumor cells can also be forced out of the niche using methods to mobilize HSCs, perhaps offering an opportunity for therapeutic intervention.105 Filgrastim is an agent that mobilizes HSCs out of the niche, and plerixafor blocks the interaction with stromal cell–derived factor 1 by acting as a CXCR4 antagonist to mobilize HSCs.106
Both agents have been approved by the FDA and may serve as a method of awakening and forcing the DTCs into circulation where they would become vulnerable to chemotherapy. A small molecule inhibitor specific to CXCR6 but not other chemokine receptors was developed for investigating the CXCL16/CXCR6 axis.107
Although the clinical utility of such an inhibitor must be investigated, the selectivity of small molecule antagonists could aid in the targeting of dormant tumor cells.
Therapeutic Opportunities for “Active” mCRPC
Although therapies to prevent the homing and establishment of mCRPC in the bone microenvironment are important clinical tactics, many patients in the clinical setting present with “active” bone metastases that cause extensive bone remodeling.
Defining the mechanisms that control cell–cell communication between the metastases and the microenvironment are also likely to reveal important therapeutic targets.
