Research Projects

Cervical cancer research – Dr Kurt Sales

Cervical cancer research – Dr Kurt Sales

Dr Kurt Sales

Dr Kurt Sales

  • Clinical Laboratory Sciences/Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty Of Health Sciences, University of Cape Town [http://www.iidmm.uct.ac.za]
  • Email: kurt.sales@uct.ac.za

Project Title:

The impact of inflammation and seminal fluid on cervical cancer progression

Project Description:

Cervical cancer is one of the most prevalent cancers affecting women in Africa. It is a disease caused by infection of the cells lining the cervix (epithelial cells) by the human papillomavirus (HPV), which is generally transmitted in male semen during unprotected sexual intercourse. Although regular cervical screening and Pap smear tests can detect abnormal cells before cancer develops, many African countries have inadequate screening programs at a National Health Service level. Recently, vaccines have been developed against HPV. These function by blocking infection of the cervix by HPV. However, these vaccines are very expensive and only available in South Africa via private medical aid. They are also of no use to the thousands of women in South Africa already infected with HPV. Therefore alternative treatment strategies are needed for these HPV infected women to prevent cervical cancer from developing.

Once HPV has infected the cells it switches on various cancer pathways inside the cell. These pathways can cause the cell to grow uncontrollably at an accelerated rate and cause cervical tumours which are red, raw and inflamed and cause a great deal of discomfort and often even bleeding. At an advanced stage they cause outgrowths into the pelvic region and distant parts of the body and often, death. The aim of our research is to establish which pathways are switched on inside the cell by HPV to cause cancer. If we can identify these pathways, we can design drugs to switch them off and prevent the progression of HPV infection to cancer. We anticipate that this approach could lead to the identification of novel therapeutic targets for women with HPV infections and precancerous lesions.

In addition to the role of HPV in cervical cancer, our research has led to the discovery that male seminal fluid during unprotected sexual intercourse can switch on pathways used by cancer cells for growth and survival. Our hypothesis is that women with HPV infections that have unprotected sexual intercourse are potentially at greater risk of cervical cancer as seminal fluid can enhance the effects of HPV in switching on the pathways used to promote cervical cancer. Therefore the aim of our study is to evaluate the impact of seminal fluid on cervical cancer progression and to identify the components of the seminal fluid and the pathways that are switched on in cancer cells that regulate growth and survival of tumours.

Summary of original objectives of the project:

Cervical cancer is the leading cause of cancer related death in women in South Africa. It is a disease associated with sexual activity. Infection of the cervical epithelium with high risk HPV 16 or 18 has been established as the main initiator of cervical cancer. However, our research has highlighted that seminal plasma can regulate genes involved in tumorigenesis in cervical epithelial cells.

My hypotheses are:

1. Following HPV infection, transcription of HPV viral oncogenes activates numerous divergent molecular and inflammatory pathways to promote and sustain cervical cancer.

2. In sexually active women, repeated exposure to seminal plasma could enhance the development of cervical cancer following neoplastic transformation of the cervix by HPV.

The aims of this proposal are to:

Aim 1: Identify the inflammatory and molecular pathways induced by HPV viral oncogenes in cervical epithelial cells which promote cervical cancer and its progression.

Aim 2: Investigate the impact of seminal plasma in regulating inflammatory pathways in the cervix and cervical cancer, which can enhance tumorigenesis.

Non-scientific report:

Cervical cancer is the leading gynaecological cancer in women in South Africa. It is a disease caused by the sexual transmission of the human papillomavirus (HPV). After HPV infects the cells of the cervix (called epithelial cells), its genetic material (called E6 and E7 oncogenes) is switched on. Once these oncogenes are switched on, the epithelial cell can replicate itself and divide uncontrollably and become cancerous. The way in which these oncogenes achieve this is poorly understood. In order to understand exactly what happens inside a cell when HPV infects the cervix, we cloned the HPV E7 oncogene from HPV. We then implanted the oncogene into cervical epithelial cells. We found that the E7 oncogene switches on genes in the epithelial cells that regulate inflammation. Chronic inflammation is the cause of more than 25% of all cancers and our research has shown that inflammatory pathways are critical regulators of cervical cancer. If left unchecked, these inflammatory pathways over time can cause the disease to progress and the cancer to become more virulent. Our new findings, showing that the HPV E7 oncogene can regulate these pathways suggest that inhibition of the E7 oncogene in cervical cancers could be a therapeutic target to prevent progression of the disease in women with cervical cancer. This might be important in regions were women are diagnosed with cervical cancer, but don’t have access to medical treatment or have to wait a long time for surgery.

In addition to HPV infection, we have also found that in sexually active women, repeated exposure to male semen at intercourse in the absence of a barrier contraceptive can also switch on inflammatory pathways. We have shown that male seminal fluid can switch on inflammatory pathways in normal cervical cells, but in cervical cancers it can promote the growth of cervical tumours. We have mapped out the precise order of events inside the cell that occurs after exposure of the cell to seminal fluid. We have identified several key proteins inside the cell, which if inhibited, can prevent these adverse effects of seminal fluid on cervical cancer growth. The main pathways that we have discovered can be inhibited with aspirin and aspirin-like drugs. Recently low dose aspirin taken on a daily basis has been shown to be protective for a variety of inflammation-induced illnesses. Our findings that aspirin-like drugs can inhibit the inflammatory pathways and effects of seminal fluid in cervical cells exposed to semen, suggest that aspirin, which is widely and cheaply available, could also benefit women with the early stages of cervical cancer, by inhibiting the inflammatory pathways that cause disease progression.

Manuscripts:

K.J. Sales, J.R. Sutherland, H.N. Jabbour, A.A. Katz (2012). Seminal plasma induces angiogenic chemokine expression in cervical cancer cells and regulates vascular function. Biochimica et Biophysica Acta – Molecular Cell Research. 1823(10): 1789-1795 (IF: 5.140)

Conferences:

K.J. Sales, J.R. Sutherland, A.A. Katz (2012). Seminal Plasma Enhances Inflammatory Pathways and Promotes Cervical Adenocarcinoma Cell Proliferation and Tumour Growth. The Role of Inflammation during Carcinogenesis Keystone Symposium, Dublin, Ireland. (Abstract 333)


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