Year

2017

Degree Name

Doctor of Philosophy

Department

Illawarra Health and Medical Research Institute

Abstract

Pancreatic and breast cancer are both architecturally heterogeneous and insidious diseases of which 90% of patients succumb due to metastasis, the spread of tumour cells throughout the body. Tumour associated fibroblasts and other stromal cells have been implicated as major facilitators of tumour invasion and metastasis. Thus, there is a strong imperative to better elucidate tumour-stromal interactions in cancer as a means to develop more effective therapies. In that regard, this thesis focused on the urokinase plasminogen activation system (PAS) in stromal remodelling and invasion using two aggressive cancer types, pancreatic ductal adenocarcinoma (PDAC) and triple negative breast cancer (TNBC), as both are well known to utilise the PAS system during their invasion processes. The main activator of PAS is the serine protease, urokinase (uPA), and its overexpression is recognised as an important biomarker of metastatic disease and a therapeutic cancer target. Receptor bound uPA activates colocalised plasminogen into the broad-spectrum protease, plasmin. The combined proteolytic and signalling events initiated by this pathway drive extracellular matrix (ECM) degradation, cell proliferation, adhesion and migration. Negative regulation of this pathway is provided at several levels, including inhibition and clearance of protease activity by naturally occurring inhibitors, such as SerpinB2 (Plasminogen Activator Inhibitor Type-2). Elevated tumour SerpinB2 expression is associated with prolonged survival, decreased metastasis, or decreased tumour growth in a number of cancer types, with loss of stromal SerpinB2 expression associated with progression. However, specific mechanisms have not been addressed. To directly interrogate the role of SerpinB2 in pancreatic and breast cancer, ex vivo and in vivo models were developed using wild-type and SerpinB2-/- murine embryonic fibroblasts (MEFs). The potential role of SerpinB2 in tumour cell invasion ex vivo was also investigated in breast tumour epithelial cells with modulated SerpinB2 expression.

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