CHARACTERIZING THE ROLE OF ANTI-GRP78 AUTOANTIBODIES IN PROSTATE CANCER AND THEIR CONTRIBUTION TO TUMOUR PROLIFERATION
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».