Targeting the Urokinase Plasminogen Activator System Combined with Chemotherapy-a Potentially Novel Therapeutic Approach for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is recognised as an exceptionally aggressive form of cancer, notorious for its limited treatment options, resistance to chemotherapy, and consequent poor prognosis. This dissertation comprehensively explores the potential of targeting the urokinase plasminogen activator (uPA) system, a well-documented factor in cancer progression as a therapeutic strategy in PDAC management, particularly in conjunction with the chemotherapeutic agent, Gemcitabine. Using publicly available datasets, we first demonstrated that upregulation of PLAU, the gene encoding uPA, is associated with poor prognosis and aggressive phenotypes. This upregulation is particularly prominent in the basal subtype of PDAC, which has a high mortality rate. We then focused on the effects of selective uPA inhibition with BB20-30F, both individually and in combination with Gemcitabine, using orthotopic xenograft models that mimic early and advanced stages of pancreatic cancer. The findings revealed that uPA inhibition with BB20-30F alone and in combination with Gemcitabine resulted in tumour growth and metastasis suppression, likely through inhibition of cancer cell proliferation, extracellular matrix degradation, and epithelial-mesenchymal transition (EMT). The combination treatment notably suppressed cancer stemness, a key factor in tumour initiation, recurrence, and resistance. Subsequently, the experiments were replicated in an immunocompetent syngeneic orthotopic model of advanced PDAC to account for the immune system's role in cancer progression. The results further validated the efficacy of uPA inhibition and the combination treatment, suggesting that these could modulate the tumour microenvironment to boost the anti-tumour immune response. Finally, we elucidated the underlying mechanisms behind these effects using in vitro co-culture experiments. uPA inhibition with BB2-30F, alone or combined with Gemcitabine, significantly decreased cancer cell proliferation and migration and promoted apoptosis. These effects were mediated by inhibiting Akt and ERK phosphorylation, suggesting the involvement of the PI3K/Akt and MAPK/ERK pathways. This comprehensive study underscores the therapeutic potential of targeting the uPA system in PDAC, either individually or in combination with existing treatments, thus opening new avenues for improving PDAC patient outcomes.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2023

Author dc:creator

• Hosen, S. M. ; https://orcid.org/0000-0001-5789-3418

• Pancreatic Ductal Adenocarcinoma (PDAC)
• Pancreatic stellate cell
• Urokinase Plamsminogen Activation System (uPA)
• PLAU
• HGF-c/Met pathway
• Therapeutic Strategy
• Tumor Microenvironment Modulation
• Orthotopic Xenograft Models
• Combination Therapy
• Syngeneic Model
• Epithelial-Mesenchymal Transition (EMT)
• Cancer Stemness
• Aggressive Phenotypes
• Immune Suppresion
• PI3K/Akt and MAPK/ERK Pathways
• Extracellular Matrix Degradation
• Basal Subtype
• Early and Advanced Stages of PDAC
• OICR
• ICGC
• TCGA-PAAD
• anzsrc-for: 321111 Solid tumours

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/25161

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/101454