Prevalence of Prostate Cancer Metastases after Intravenous Inoculation Provides Clues into the Molecular Basis of Dormancy in the Bone Marrow Microenvironment

Abstract

Bone is the preferred metastasis site of advanced prostate cancer (PCa). Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb. We therefore speculated whether the environment of the forelimb bones is not permissive for the growth of PCa. Consequently, data on tumor prevalence were normalized to account for the number of PCa cells arriving after intravascular injection, marrow cellularity, and number of hematopoietic stem cell niches. None of these factors were able to account for the observed differences in tumor prevalence. An analysis of differential gene and protein levels identified that growth arrest specific-6 (GAS6) levels were significantly greater in the forelimb versus hindlimb bone marrow. When murine RM1 cells were implanted into subcutaneous spaces in immune competent animals, tumor growth in the GAS6(-/-) animals was greater than in GAS6(+/+) wild-type animals. In an osseous environment, the human PC3 cell line grew significantly better in vertebral body transplants (vossicles) derived from GAS6(-/-) animals than in vossicles derived from GAS6(+/+) animals. Together, these data suggest that the differences in tumor prevalence after intravascular inoculation are a useful model to study the molecular basis of tumor dormancy. Importantly, these data suggest that therapeutic manipulation of GAS6 levels may prove useful as a therapy for metastatic disease.

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

“…A cohort of serum samples from patients with progressive advanced castration-resistant prostate cancer was assessed in vossicles where tumors overgrew the bone scaffolds (31). Another example of the vossicle model highlighting the bone microenvironment in tumor progression revealed that ablation of the osteoblast niche hindered prostate cancer growth in tumor vossicles (17).…”

“…Vossicle (vertebral body) subcutaneous RM1-iC9 tumors. The vossicle model, which provides an osseous scaffold for tumor growth in a bone microenvironment, has been previously described (9,31). Detailed description is provided in Supplemental Methods.…”

“…As CXCL5 was found to increase with cancer cell death and efferocytosis in the tumor Cancer cell death accelerates tumor progression and increases tumor CXCL5 levels. To investigate how efferocytosis of cancer cells affects prostate cancer tumor progression in bone, an osseous implant vossicle model was used (9,17,31). Apoptosis-inducible RM1-iC9 cells were coimplanted with vertebral bodies (vossicles) of 7-day-old C57BL/6J mice into the subcutaneous compartment of 7-week-old C57BL/6J mice ( Figure 4A).…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…37 Along with this notion, in mice inoculated with prostate cancer cells, tumor growth is mainly observed in bones expressing low levels of GAS6 (forelimb), whereas tumors rarely grow in bones expressing abundant GAS6 (hindlimb). 38 Moreover, PC3 and DU145 cells, which are proliferating in the bones, express relatively low levels of Axl, compared with when they are in a dormant state. 39 These findings suggest that the osteoblastic niche controls dormancy of disseminated prostate cancer through a GAS6/Axl axis.…”

The Bone Microenvironmental Effect in the Dormancy of Cancer

“…Similar results were observed in osseous environment, the human PC3 cell line was injected into vertebral body transplants (vossicles) and tumors formed in vossicles derived from GAS6 −/− animals were greater than those from GAS6 +/+ animals. So, they proposed that GAS 6 can induce the dormancy of cancer cells [34]. Meanwhile, Shiozawa Y. et al not only verified that GAS 6 can regulate PCa cell mitotic cycle, and pointed out that GAS 6 was secreted by osteoblasts in the BM niche [35].…”