Evaluating Senescent Stromal Fibroblasts as a Promoter of Prostate Cancer Lethality to Inform a Paradigm Shift in Prognostic, Predictive, and Therapeutic Strategies
Abstract
Prostate cancer is a disease of aging and we don’t know why. If we understood the biological link between the aging prostate and prostate cancer, we would be able to prevent or intervene. Prostate tissue has two types of cells, epithelial and stromal. Epithelial cells make PSA and can become cancerous. Stromal cells include fibroblasts (connective tissue cells) and smooth muscle cells. For unknown reasons, aging prostate fibroblasts can lose their ability to replicate, a state called senescence. One possible reason is shortening of the telomeres – the ends of the chromosomes. Telomeres shorten each time cells replicate, which acts as a clock that can signal the onset of senescence, although cells may senesce for other reasons. Again, for unknown reasons, some of fibroblasts that are senescent begin secreting molecules including cytokines, which can summon inflammatory cells and promote the growth and survival of nearby cancer cells. This inflammation could be problematic: in our prior research, prostate inflammation, most of which was in the stroma, was associated with a higher risk of prostate cancer, and men with inflammation were more likely to have high-grade disease. Short telomeres may also be problematic; we found that men with shorter stromal cell telomeres were more likely to be diagnosed with prostate cancer, and in men surgically treated for prostate cancer, those with shorter stromal cell telomeres were more likely to later develop metastases and die. Given this rationale, we hypothesize that the aging prostate with senescent cytokine-secreting fibroblasts influence whether a man develops prostate cancer, whether a man with prostate cancer later develops metastases despite surgery that should have cured him, and whether a man who recurs after his prostatectomy and is treated with salvage radiation with or without anti-androgen drugs later progresses to metastasis. We also hypothesize that cytokine-secreting fibroblasts are more common in Black men, whose risk of dying of prostate cancer is substantially higher. Our objective is to test these hypotheses by conducting innovative research with four aims: 1. Test whether men whose prostates have senescent cytokine-secreting fibroblasts are more likely to develop prostate cancer. We will use a unique resource: prostate tissue from men without prostate cancer who had a biopsy despite normal PSA/DRE because they were in a trial; we will determine whether years after the trial they developed prostate cancer by linkage to Medicare claims data. 2. Test whether surgically treated men whose prostates had senescent stromal fibroblasts are more likely to recur and progress to metastasis. We will use a resource that we generated that is available in the PCBN. 3. Test whether surgically treated men who were later were given salvage treatment whose prostates have these fibroblasts are more likely to progress to metastasis. We will also test whether the presence or absence of these fibroblasts indicates whether adding an anti-androgen drug to radiation therapy is beneficial. We will generate a new resource from existing medical records and archived tissue, which we will make available in the PCBN. 4. Determine whether having these fibroblasts differ in Black and White men with prostate cancer. We will use two PCBN resources designed to study why Black men are more likely to have aggressive prostate cancer. We are responsive to the PCRP by addressing the challenge, “Define biology of lethal prostate cancer to reduce death,” by evaluating these fibroblasts as lethal disease markers. Our proposed research is designed to inform critical clinical needs for lethal prostate cancer and is applicable to men at risk for lethal prostate cancer, men with localized disease at risk for metastasis, and men who receive salvage treatment for rising PSA after surgery at risk for metastasis, including Black men. We expect to inform the pressing clinical need for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010264
Entities
People
- Elizabeth A Platz
Organizations
- Johns Hopkins University
- United States Army