Therapeutic Opportunities on the Horizon

Treatment options to extend the overall survival of pa­tients diagnosed with mCRPC remains a major clinical challenge.

Therefore, understanding the factors that drive the process of metastasis, the homing of the me­tastasis to organs (eg, bone), and how prostate cancer cells form life-threatening active metastases once in the bone warrants extensive research to generate new therapies to cure the disease.

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Although metastasis is classically thought of as a linear sequence of events beginning with the dissemination and invasion of tumor cells from the primary site and ending with proliferation at the metastatic site, recent evidence suggests that the first steps of metastasis can occur before a patient’s tumor is diagnosed (Fig 2).75

This “step 0” of the metastatic cascade results in the non­random priming of future sites of metastasis, a concept known as the “premetastatic niche.”

(To view a larger version of Figure 2, click here.)

Premetastatic Niche

Primary tumor-derived factors have been implicated in the development of premetastatic niches in distant organs.76

Through a series of in vivo experiments, it was illustrated that conditioned media derived from highly metastatic cancer cells lines, such as the B-16 melanoma cell line, could stimulate the mobilization of bone marrow–derived VEGF receptor 1+ VLA4+ Id3+ hematopoietic precursor cells to develop premeta­static niche sites, including the lungs, liver, spleen, kidney, and testes.76

Cancer-derived exosomes have been implicated as the mechanism for facilitating long distance, tumor–stroma interactions and initiat­ing the premetastatic niche.77 Exosomes are microve­sicles measuring 30 nm to 100 nm that contain a variety of functional proteins and messenger/micro RNAs.78 In the context of premetastatic niche forma­tion, B16-F10–derived exosomes have been labeled and shown to “home” to common sites of melanoma metastasis.75

Furthermore, in the premetastatic niche, exosomes can educate bone marrow–derived cells to support metastatic tumor growth via the horizontal trans­fer of the c-MET protein.75 c-MET inhibitors, such as cabozantinib, could be used to prevent the development of premetastatic niches and, thus, mitigate the ability of cancers to metastasize to new sites.

Exosome shedding has also been demonstrated in prostate cancer, and studies have shown the pres­ence of microvesicles termed oncosomes (0.5–5 μm) in prostate cancer–conditioned media. Oncosomes contain a variety of signal transduction proteins, including Akt and Src, and can interact with tumor and stromal cells to elicit disease-promoting responses.79

In addition, a correlation exists between a Gleason score higher than 7 and the number of oncosomes present in patient plasma.80 Based on these findings, it is plausible that prostate cancer–derived exosomes can play a role in the formation of premetastatic niches in the bone microenvironment. Emerging evidence also suggests that prostate cancer cells homing to the bone microenvironment can occupy the endosteal niche, the vascular niche, or both.81

Defining Factors Controlling the Homing of Bone Metastatic Castration-Resistant Prostate Cancer

An unsolved question regarding metastasis is why prostate cancer has such a predilection for the bone microenvironment. More than a century ago, Paget82 formulated the “seed and soil” hypothesis to address this question.

His hypothesis suggested that metastasis is a challenging process that requires “fertile soil” for outgrowth but begins long before the “seed” meets the “soil.”82 Ewing83 challenged Paget’s hypothesis in the 1920s, proposing that metastasis was instead de­pendent on anatomy, vasculature, and lymphatics.

Metastasis by anatomy would become the accepted model until the 1970s when modern experiments re­kindled interest in the “seed and soil” hypothesis, notably observing that circulating tumor cells reach the vasculature of all organs, but only certain organs are receptive for metastasis.84,85 In reality, prostate to bone metastasis occurs by a blend of both hypotheses: It metastasizes first to the pelvic lymph node and then to sites in the bone, including iliac crests, sacrum wings, L1 to L5 vertebrae, T8 to T12 vertebrae, ribs, manubrium, humeral heads, and femoral necks.86

Although 15% to 30% of prostate to bone metastases are due to cells traveling through the Batson plexus to the lumbar spine, it is clear that molecular factors, such as chemokines and integrins, underpin the pro­pensity for prostate cancer cells to metastasize to the skeleton.11 Elucidating those factors could help identifytify new therapies to prevent bone metastatic CRPC.

Bone is the home of regulatory sites for hemato­poietic stem cells (HSCs), which are cells localized to the vascular and endosteal niches where they either await hematopoietic demand or reside in a quiescent state.81 One well-defined signaling axis implicated in metastasis is that between stromal cell–derived factor 1/CXCL12 and its receptor CXCR4, a system normally utilized by HSCs homing to the niche.87

CXCL12 expression is increased in the premetastatic niche, and studies in prostate cancer have demonstrated that tumor cells with high bone-homing capacity express CXCR4 and CXCR7 to parasitize the HSC niche.76,88,89 Furthermore, CXCR4 expression correlates with poor prognosis.90 Additional axes, including MCP-1/CCR2 and CXCL16/CXCR6, have also been found to con­tribute to the progression of prostate cancer through increases in proliferation, migration, and invasion.91,92