CHARACTERIZING THE ROLE OF ANTI-GRP78 AUTOANTIBODIES IN PROSTATE CANCER AND THEIR CONTRIBUTION TO TUMOUR PROLIFERATION
Bibliographic record
Abstract
Prostate Cancer Canada estimates that sixty-five Canadian men will be diagnosed with prostate cancer (PC) daily, thus, PCa is the most frequently diagnosed cancer and the second leading cause of caner-related deaths in men. Currently, the etiology of PC remains under investigation and mechanisms of its growth and proliferation are yet to be fully characterized. This gap in knowledge places patients diagnosed with PC at risk of being under- or over-treated, and thus this thesis was dedicated to better understand the pathology of this disease. We and others had demonstrated that the endoplasmic reticulum (ER)-resident molecular chaperone, termed GRP78, can translocate to the cell surface in some cancer cells, including PC, bladder, breast and leukaemia malignancies. In PC, cell surface GRP78 can bind to different ligands and elicit new functions such as activation of pro-survival and/or pro-apoptotic pathways. Furthermore, studies have found that cell surface GRP78 acts as an antigenic receptor leading to production of anti-GRP78 autoantibodies. The overall objective of my PhD thesis was to study and identify new functions for cell surface GRP78 and define its impact PC tumour growth and proliferation. Based on my findings, we report a new function of cell surface GRP78 where it can modulate the activity of the major initiator of the coagulation cascade, tissue factor (TF), following the binding of anti-GRP78 autoantibodies to cell surface GRP78. Here, we demonstrated that the binding of anti-GRP78 autoantibody to cell surface GRP78 elicits an increase in cytosolic Ca2+ concentration, and leads to TF activation on intact bladder carcinoma cells (T24/83). This finding was preceded by establishing a new technique of real-time measurement of TF activity in a continuous manner on intact cells. In addition to its function as the major initiator of the coagulation cascade, TF contributes to angiogenesis in cancer biology. This raises the question whether anti-GRP78 autoantibodies can activate TF and contribute to enhanced tumour progression. Using the NOD/SCID mouse model, anti-GRP78 autoantibodies were shown to accelerate tumour growth of implanted DU145 PC cell line xenograft. This observed accelerated rate of tumour growth was reversed using a TF knock down DU145 cell line, emphasizing the requirement of TF expression to mediate this process. Finally, we demonstrate the ability of heparin and low molecular weight heparin molecules to interfere with the binding of anti-GRP78 autoantibodies to cell surface GRP78; in vitro and in vivo investigations demonstrate reduced TF activity and tumour progression, respectively. This likely involves the ability of heparin and low molecular weight heparin to bind to a reported heparin binding region in cell surface GRP78 that is also known to harbor the epitope for the anti- GRP78 autoantibodies. To our knowledge, this novel finding is the first to show a direct role for an autoantibody produced by the host immune system as the driver for tumour progression via TF. These findings have the potential to improve management of this disease which will help in improving quality of life for patients affected with PC.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".