Metastasis of Prostate Cancer
The most prevalent site for metastasis of prostate cancer is in bone, occurring in up to 80% of affected individuals. Upwards of 90% of these patients die as a result of prostate cancer with bone involvement, and there are currently no effective treatment modalities available (Jones et al., 2019). Metastatic prostate cancer that has spread to the bone represents a form of cancer for which prognosis remains poor and morbidity remains high. It is well established that efferocytosis—the process by which macrophages phagocytose apoptotic cells—induces a pro-inflammatory microenvironment in bone-metastasized prostate cancer (Roca & McCauley, 2018). Inflammation from efferocytosis ultimately supports tumorigenesis, marking an important process for cancer research. The mechanisms for this cascade are explored in the groundbreaking research article “Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.” Dr. Jones and her colleges empirically identify the role that prometastatic macrophages play in prostate cancer metastasis. CXCL5 is specifically investigated as a key proinflammatory cytokine that activates both the Stat3 and NF-?B signaling pathways, effectively presenting macrophage reprogramming and CXCL5 inhibition as potential targets for therapy. While results may influence treatment of other aggressive cancers, such as breast cancer, the research of this article was limited in scope to prostatic cancer.
Research within the article examines six relationships CXCL5 shares with metastatic prostate cancer. Research is conducted with murine prostate cancer RM1 cells, PC3 cells, and MC3t3-E1 subclone 5 (MC4) cells. Vossicle tumors RM1-iC9 tumors, intratibial injection models, and human mononuclear cell isolation are all models employed by the study. Statistic analyses use a P less than 0.05, except for the Kruskal Wallis rank test which uses a P of less than 0.0083. One and 2-way ANOVA were also employed for making comparisons, as well as TRACER data.
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The first relationship examined is that of efferocytosis of apoptotic cancer cells and the subsequent induction proinflammatory cytokines. According to the research, bone marrow-derived macrophages (M?s) in murine models express different cytokines when apoptotic cancer cells undergo efferocytosis. CXCL5 was one such cytokine activated in subjects with apoptotic cancer cells that was not observed in subjects with apoptotic noncancer cells. Transcriptional regulation was confirmed with PCR mRNA expression analyses. Further testing indicated that efferocytosis of the apoptotic cancer cells was responsible for a unique yet consistent inflammatory response.
The second association examined is that of inflammation caused by CXCL5 and the activation of Stat3 and NF-?B signaling pathways. This was performed by creating apoptosis-inducible prostate cancer cells (RM1-iC9) from murine RM1 cells. Clearing of these cells by efferocytosis identified NF-?B as an important transcription factor that exhibited an increase of activation by phosphorylation. Western blotting, a technique used to isolate and quantify individual proteins, indicated that Stat3 signaling was also activated.
Subsequently, the research aims to establish that death of cancer cells is associated with enhanced tumor progression and a surge 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 is 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 from the cancer itself. Mice without the CXCL5 allele increased CD86+ signaling, corresponding to an increase of 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 transitions from a murine model to investigate human serum levels of patients with prostate cancer with skeletal metastasis. The focus shifts 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.
The research is as exciting as it is innovative, as it surely will open many doors in the realms of oncology and medicine. The research already highlights many prospective areas in which treatments can be developed. Roca and McCauley, two authors of the article have already gone on to propose five specific targets for treatment as a result of the research. They include M? macrophage reprogramming, inhibition of Stat3 and NF-?B signaling, inhibition of CXCL5 and its receptor CXCR2, inflammation pro-resolving mediators, and immunosuppression immune checkpoint inhibitors (Roca & McCauley, 2018). Dr. Jones has already published additional research on M? macrophages, proposing Trabectin as a means to discourage the proliferation of M2 macrophages thereby stopping the associated signaling pathways at the source. This has already been performed with some success in murine models (Jones et al., 2019). While this is novel, and could soon be implemented to improve patient prognosis, investigation of the remaining four targets for treatment should still be investigated for the outcome with the fewest untoward effects.