The most Prevalent Site for Metastasis of Prostate Cancer is in Bone

Clearing of these cells by efferocytosis identified NF-?B as an important transcription factor that exhibited an increase in activation by phosphorylation. Western blotting, a technique used to isolate and quantify individual proteins, indicated that Stat3 signaling was also activated. Subsequently, the research aimed to establish that the death of cancer cells is associated with enhanced tumor progression and a surge in CXCL5 levels within the tumor. Put simply, apoptosis induced by VEH and AP dimerizers and efferocytosis by M2 macrophages did, in fact, reveal significant acceleration of tumorigenesis. The subsequent tumor growth coincided with high levels of CXCL5 expression in vitro. This testing indicated that the mechanism of tumor growth is a response to the pathways at play in the local microenvironment. CXCL5 was then investigated solely for its role as a hallmark inflammatory cytokine, responsible for the progression of the tumor. This was performed by testing the progression of tumors in CXCL5 positive (wild type) and CXCL5 deficient mice. In doing so, CXCL5 proliferation was determined to be independent of the cancer itself. Mice without the CXCL5 allele increased CD86+ signaling, corresponding to an increase in T lymphocyte activation not seen in CXCL5 positive mice. Moreover, CXCL5 negative mice did not present as immunosuppressed.

Ultimately, the research was effective in tying CXCL5 production to an environment favorable to tumor growth. Conversely, the study went on to show that a deficiency in CXCL5 hinders the progression of tumors. CXCL5 positive mice experienced an escalation of bone osteolysis from tumor growth. This resulted both from increased efferocytosis and the osteolysis of RM1 cancer cells, as both populations of mice maintained similar levels of osteoclasts. CXCL5 negative mice were found to have better bone volume and reduced spacing. Histological staining of tumors from CXCL5 negative mice reflected a marked decrease in tumor progression, thus cementing the role of CXCL5. Lastly, the research transitioned from a murine model to investigate human serum levels of patients with prostate cancer with skeletal metastasis. The focus shifted to peripheral mononuclear cells, defining them as immune cells in circulation that replenish resident cells. Individuals with skeletal metastasis were examined to find an increase in circulating phagocytic immune cells due to the presence of tumor cells in circulation. Analysis of blood samples proved that nonclassical (CD16+) phagocytes rose in these individuals. Additionally, CD14+ monocytes from these same patients exhibited increased efferocytosis, evidenced by apoptotic-mimicry beads. Moreover, considerably higher CXCL5 levels were found in patients with skeletal metastasis. This suggests that there is an inherent link between increased CD16+ and CD14+ monocytes, CXCL5 serum levels, and tumor progression.

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