Prostate-derived fibroblast ‘bystander cells’, proteinase signalling and prostate cancer cell regulation
Dr. Morley D. Hollenberg, University of Calgary Cumming School of Medicine
Eric Hyndman, Prostate Cancer Centre, Rocky View Hospital
Lead Investigator Bio:
Dr. Hollenberg is a Doctoral trained physician with an MSc (chemistry) from the University of Manitoba, a D. Phil. (Pharmacology from the University of Oxford) and an MD from Johns Hopkins University School of Medicine. His Medical Internship at the Johns Hopkins Hospital was followed by a Research Fellowship in the Department of Pharmacology & Therapeutics at Johns Hopkins, working on the molecular pharmacology of receptors for insulin and epidermal growth factor. He was recruited to the University of Calgary Faculty of Medicine in 1979, as the head of the Department of Pharmacology & Therapeutics, serving as Department Head from 1979 to 1989, and concurrently as the Chair of the Endocrine Research Group. Currently, he is an Associate-Director of the University of Calgary Cumming School of Medicine MD-PhD-MSc Leaders in Medicine programme. With continued CIHR funding since 1979, Dr. Hollenberg is a Principal Investigator for projects dealing with the molecular pharmacology of growth factor and G-protein-coupled receptors that are involved in diseases ranging from arthritis to colitis and prostate cancer. With over 20,000 citations to date and between 50-100 downloads/week (Research Gate), Dr. Hollenberg’s work was ranked in the Thompson Reuters 2014 top 1% of research citations in pharmacology world-wide, with a listing in ‘The World’s Most Influential Scientific Minds: 2014’ (ScienceWatch.com). A main focus in his lab is on the mechanisms whereby microenvironment proteinases drive inflammatory disease and cancer. Dr. Hollenberg’s laboratory is internationally recognized for its sustained contributions of ‘firsts’ in the area of receptor molecular pharmacology, including 1. molecular characterization of the EGF receptor (1973: PMID 4355377)**, 2. documentation of multiple receptors for thrombin (PARs, 1993: PMID 8391118), 3. documenting the inflammatory actions of PAR1/2 activation (1999: PMID 10205017; 10455252) and most recently 4. demonstrating ‘biased’ PAR1/2 signaling by inflammatory proteinases (2009,2011,2013: PMIDs 19605524, 21576245, 24052258). These findings are directly relevant to the pathophysiology of many diseases ranging from arthritis and prostate cancer, which is the subject of this application, to neurodegenerative disease, dermatitis and cardiovascular disease. The data are therefore of direct therapeutic potential (PMID 22212680).
Prostate cancer progression is now known to depend on the non-tumour ‘bystander cells’ surrounding the tumour cells. The mechanism(s) whereby non-tumour-bystander-cells affect tumour cells is not yet understood. We propose that this effect of bystander cells on tumour cells, or of tumour cells on the bystander-cells, is mediated by 1. Substances secreted by the bystander-cells and/or tumour cells that cross-over and regulate their neighbouring cells or 2. The bystander-cell-secreted material on which the tumour cells grow. This bystander-cell-secreted material on which tumour cells ‘sit/grow’ affects tumorigenesis. Neither the nature of the bystander-cell-secreted factors affecting prostate cancer cells nor the stimuli that promote secretion of compounds from the bystander-cells are yet known.
We hypothesize that these bystander-cell/tumour-cell-secreted compounds cause cell-to-cell communication conveyed by digestive enzymes that activate cell signals by cutting/turning-on a specialized ‘cell-surface-receptor-on-switch’ (a digestive-enzyme-activated-receptor) on both the tumour cells and non-tumour bystander cells.
We will evaluate these possibilities using human prostate-tissue-derived bystander-cells, determining 1.If they secrete enzymes that regulate the ‘on-switch’ on prostate-cancer-derived cells and 2.If the ‘on-switch’ in prostate-derived bystander-fibroblasts responds to tumour-cell-secreted digestive enzymes by producing secreted material on which the tumour cells grow more aggressively. The data may reveal new ways to control prostate tumour development.
Prostate cancer progression is not solely dictated by the cancer cells themselves but also by the non-tumour (stromal) cells, including fibroblasts/myofibroblasts. The stroma surrounding the tumour can augment tumor cell epithelial-to-mesenchymal transition (EMT), invasion, and chemotherapy resistance. The impact of the stroma on tumor cell behaviour may be mediated 1.) by factors produced by the stromal cells themselves and secreted into the microenvironment or 2.) through tumor cell interactions with the extracellular matrix deposited by the stromal cells. Neither the role nor the identity of the stromal-cell-secreted factors that affect prostate cancer cells, nor the tumour-derived stimuli that promote stromal cell signalling and matrix production are yet known. However, a cellular target has been identified that plays an important role in integrating these signals in both stromal and tumor cells: proteinase activated receptors (PARs).
Thus, we hypothesize that stromal-cell-secreted proteinases and matrix components regulate microenvironment proteolytic signalling mediated by PARs.
It is our objective to utilize human prostate-tissue-derived stromal cells, to determine: 1.if they secrete PAR-activating proteinases that can affect prostate-cancer-derived-cell signalling (PC3/DU145/LNCaP cells); and 2.If the prostate-derived stromal cells can respond to PC3/DU145/LNCaP-secreted PAR-regulating proteinases by increasing matrix production, that in turn can affect PC3/DU145/LNCaP-cell growth and function.
Impact on prostate cancer patients:
In principle, the results may pave the way to identifying new therapeutic targets for preventing the growth and spread of prostate cancer.