Molecular Epidemiological Research on Key Drivers of Breast and Prostate Cancer Progression

Ongoing Research by the Glynn Group (Email: sharon.glynn@nuigalway.ie

Research Focus 1: Inflammation in Breast and Prostate Cancer
Chronic inflammation and infection are major mediators of cancer initiation and cancer progression. Key mediators of inflammation-induced cancer include NFkB, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs, which in turn exert their effects though changes in cell proliferation, apoptosis, cellular senescence, DNA mutation rates, DNA methylation, cell invasiveness and angiogenesis. Together these species present the ideal targets for early detection, diagnosis, prediction of outcome and also therapeutic targets. Nitric oxide (NO) the product of nitric oxide synthase 2 (NOS2) can influence tumour biology in various and sometimes dichotomous ways. Genetic ablation of NOS2 increases mammary tumour latency and inhibits lung tumour development in mouse models of cancer. These genetic findings demonstrate that NOS2 can have tumour promoting activities. However, NOS2 expression or other forms of NO exposure are not always tumour promoting, and there are many examples where exposure to NO either delayed or inhibited tumour growth and metastasis. Because the effects of NO are strictly concentration-dependent with high concentrations causing cytostasis and apoptosis, at least some of the observed differences are likely explained by a difference in levels of NO exposure.

Research Focus 2: The Prostate Cancer - Bone Marrow Mesenchymal Stem Cells Para-endocrine Axis in the metastatic tumor microenvironment
Mesenchymal stem cells (MSC) are multipotent stem cells that can differentiate into osteoblasts, chondrocytes, adipocytes, myocytes and neurons. They can be sourced from the bone marrow (BM) stroma, adipose tissue and dental pulp, and are also found in circulation and are known to home to inflammatory sites. Due to their capacity to home to injured tissue, research has suggested a reparative function for MSC in multiple tissues. In recent studies it has been shown that MSC can also home to tumour sites and contribute to tumour growth and progression. MSC have been shown to increase the metastatic potential of tumour cells by promoting their migration and invasion as well as having a role in the development of a metastatic niche at the secondary site. BM-MSC may also contribute to tumour growth by differentiating into cancer associated fibroblasts (CAFs), which form part of the tumour microenvironment. Additionally BM-MSCs are intrinsically radio- and chemo-resistant due to a heightened DNA damage response, and thus may contribute to treatment resistance. Our preliminary studies demonstrate that considerable baseline variations exist in the secretomes of primary BM-MSCs which impact the magnitude of their response to PrCa cell lines, and vice versa. This indicates that inter-patient BM-MSC variation, may impact on tumour microenvironment dynamics, influencing a patients risk of metastasis, and potentially therapeutic response. Our preliminary data has also identified members of the BM-MSC secretome that induce PrCa cell migration in a dose dependant manner, using recombinant growth factors at the concentrations produced by the BM-MSCs.

Research Focus 3: Human Endogenous Retrovirus Activation

In recent years scientists have observed that several tumor types, including prostate cancer, show increased expression of human endogenous retrovirus (HERV) when compared to normal tissue. Why are these HERVs of interest? The HERVs originated from germ cell infections by exogenous retroviruses during the course of evolution and became incorporated into the human genome. These elements are widely dispersed throughout the genome and are estimated to comprise of greater than >8% of genomic material. Over 20 HERV families have been identified to date, the majority of which are defective due to mutations, deletions or termination signals within coding regions. The HERV-K family, evolutionarily the youngest HERV, is the only HERV family with complete open reading frames for all viral genes, and thus are the most likely to be biologically active and potentially pathogenic. Several questions need to be asked about HERV-K in prostate cancer. Is HERV-K activation a bystander effect in prostate cancer or is it linked to active prostate progression; can it distinguish indolent from aggressive disease? What is the major activator of HERV-K expression in prostate cancer? Does chronic inflammation in prostate tissues lead to the activation of HERV-K expression or does activation of HERV-K lead to tissue inflammation and subsequent carcinogenesis? Pockets of inflammation are often observed in prostate tissues that are not actually cancerous tissue but are thought to be associated with increased risk of prostate cancer.

Current Research Staff

Dr. Pablo Garrido-Cuesta (Breast Cancer Now Funded)

Dr. Karen O’Leary (Irish Cancer Society Funded)

Ms. Nessa Keane (Breast Cancer Now Funded)

Current Postgraduate students

Amy Burke (PhD Candidate)

Carol Johnson (PhD Candidate)

Sarah Ridge (PhD Candidate)

Ronan Downey (Irish Research Council PhD Candidate)

Husnain Ali (Cancer Care West-Hardiman PhD Candidate)

Former Postgraduate students

Aidan Toner (PhD – Graduated June 2015)

Stephen Gardiner (MSC in Cancer Research – Graduated 2013)

Michelle O’Leary (MSC in Cancer Research – Graduated 2014)

Undergraduate research project students

Eoin Dervan                                    (BSc Pharmacology 4th year project)

Jack Brady                                       (BSc Pharmacology 4th year project)

Ailbhe Ni Chosgora                          (BSc Biochemistry 4th year project - 2014 Global Undergraduate Research Festival - Highly Commended)

Laura Cunningham                         (BSc Biochemistry 4th year project - 2014)

• For a list of Dr. Sharon Glynn’s publications, please click here:

http://www.nuigalway.ie/medicine-nursing-and-health-sciences/staff-profiles/sharonglynn/

 

The Glynn Lab is Funded by Breast Cancer Now and the Irish Cancer Society