Oncostatin M Receptor Overexpression Promotes Tumour Progression in Squamous Cell Carcinoma, via Hypoxia Signalling and Multiple Effects on the Tumour Microenvironment
Cervical cancer still represents the fourth most common cause of cancer deaths in women
worldwide. Human papilloma virus (HPV) infection plays a role in cervical carcinoma initiation,
but other genomic changes are needed for pre-malignant abnormalities to fully develop to
cancer. This often happens through genomic instability caused by the virus oncoproteins.
Several integrative genomic analysis studies have found that one of the most common
imbalances in cervical squamous cell carcinoma (SCC) is copy number gain and amplification
of chromosome 5p. In this region, copy number gain of the OSMR gene was found to correlate
significantly with adverse outcome independent of the tumour stage (p=0.046). Furthermore,
this copy number gain correlated with Oncostatin M receptor (OSMR) overexpression and
sensitised these cells to Oncostatin M (OSM) leading to increased Signal transducer and
activator of transcription 3 (STAT3) phosphorylation, cell migration, invasion and proangiogenic
signalling.
The aim of this PhD project was to study the role of OSMR overexpression in the SCC tumour
microenvironment (TME) and tumour growth in vivo and to study the role of hypoxia
inducible factor driven hypoxia signalling in OSMR overexpressing SCC cells and their tumour
microenvironment. OSMR overexpression was found to sensitise tumour cells to induce
Hypoxia inducible factor 1a and 2a (HIF1a, HIF2a) signalling in normoxic conditions, to
promote pro-angiogenic signalling. Furthermore, hypoxic conditions were found to enhance
OSM signalling in OSMR overexpressing cells leading to increased expression of markers of
epithelial to mesenchymal transition, angiogenesis and migration. In the SCC tumour
microenvironment, OSMR overexpression was found to sensitise tumour cells to OSM
secreted from macrophages and other immune cells leading to improved tumour growth,
angiogenesis and STAT3 activation at the tumour site. Removal of OSMR from either tumour
cells or tumour microenvironment led to reduced tumour growth and angiogenesis, along
with increased tumour necrosis.
I conclude that OSMR overexpression is an important driver of SCC tumour progression and
malignancy via STAT3- and HIF-driven signalling and removal of it from either tumour cells or
tumour microenvironment drastically hampers tumour growth in vivo. Based on the results
of this study, OSMR blockade is a potential novel therapeutic option in advanced SCC.Departmental scholarshi