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School of Science, Psychology and Sport

Nuzhat Ahmed honours project

Elucidating the role of monocytes/macrophages in promoting metastasis and chemoresistance in ovarian cancer cells

Supervisors: Professor Nuzhat Ahmed, Dr Dilys Leung, Dr Elif Kadife & Dr Morgan Wallace

Project Site: Fiona Elsey Cancer Research Institute, Ballarat Park Central, Ballarat 3353.

Hypothesis- Tumour infiltrating monocytes/macrophages promotes ovarian cancer metastasis and chemoresistance.

Specific aims- (i) To determine whether the presence of differentiated macrophage cell lines (M1 or M2) or macrophages isolated from ovarian cancer patients can alter the growth, invasive properties, cancer stem cell (CSC) enrichment and response of ovarian cancer cell lines to chemotherapy in a co-culture model.

(ii) To determine whether established ovarian cancer cells under the influence of hypoxia and chemotherapy treatment can alter the phenotype of co-cultured monocytes/macrophages.

Background/Rationale: Ovarian cancers are aggressive malignancies characterised by high relapse rates and resistance to chemotherapy.Macrophages are versatile immune effector cells that play an essential role in the regulation of local immune responses in tissues. Macrophages differentiate from monocytes and show remarkable functional plasticity, altering their phenotype and function in response to cytokine signals from their environment. Classically M1 macrophages produce pro-inflammatory cytokines and reactive oxygen/nitrogen species critical for host defence and tumour killing. On the other hand, M2 macrophages induce anti-inflammatory response, suppress host defence mechanisms and promote tumourigenesis through angiogenesis and matrix remodelling. Hypoxia is a common feature of solid tumours, such as ovarian cancer and it is now well established that hypoxia shapes and induces specific phenotype of tumour cells by promoting immune evasion, chemoresistance, angiogenesis, tumour cell survival and metastasis. Hypoxia has also been reported to change the phenotype of macrophages from M1 to M2 state. Tumour associated macrophages (TAM) typically have an M2 like phenotype and their presence has been associated with poor prognosis is many cancer settings. The infiltration of macrophages in high-grade ovarian tumours has been reported and recent studies in our laboratory suggest significant elevation of infiltrating CD163+ (M2-type) macrophages in high-grade ovarian tumours compared to benign ovarian tumours. These findings highlight a need to better understand how the interactions between tumour cells and macrophages in ovarian cancer might influence tumour growth and metastasis. This study will develop an in vitro co-culture model that will allow us to assess changes in both macrophages and cancer cells in the presence or absence of hypoxia and exposure to chemotherapy treatment (cisplatin and paclitaxel).

Methods: The proposed study will compare the inherent traits and chemotherapy response of ovarian cancer cell lines in the presence and absence of monocyte/macrophage cell lines in a co-culture model, under hypoxic or normoxic conditions, with or without added chemotherapy treatments. In addition, we will assess phenotypic and functional changes to the monocytes and/or macrophages (M1 or M2) exposed to ovarian cancer cell lines under these conditions to see whether hypoxia and chemotherapy induced changes in ovarian cancer cells cause altered macrophage behaviour.

This study may be extended to look at primary monocytes or macrophages isolated from the ascites or tumours of ovarian cancer patients. Their effect on isolated primary ovarian tumour cells, untreated ovarian cancer cell lines and chemotherapy-treated CSC-like cells will be studied in the presence and absence of hypoxia. Differences in the biological phenotype of ovarian cancer cells and monocytes/macrophages co-cultured in the presence and absence of chemotherapy and hypoxia will be assessed by methods such as Western blot, zymography, quantitative PCR, immunofluorescence, flow cytometry and MTT assays.

Human ethics for this project has been approved by Ballarat Health Services.