A growing body of work implicates chemokines and their receptors in the progression of various types of cancer, including breast cancer. However, as potent chemotactic factors for leukocytes, chemokines also have the potential to enhance anti-cancer immunity. Evidence suggests that the chemokine CXCL12 and its receptors may be important in a number of aspects of breast cancer progression and site-specific metastasis. Another chemokine, CXCL16, has been identified as a specific chemotactic factor for Type Ipolarised T lymphocytes, which are major effectors of cell-mediated immunity and hence efficacious anti-tumour immune responses. The aim of this study, therefore, was to further elucidate the roles of CXCL12 and CXCL16 in breast cancer development and metastasis. To achieve this, wild-type CXCL12 and CXCL16 and antagonists of CXCL12 and CXCL16 activity, CXCL12[subscript](P2G) and CXCL16[subscript](9-220) respectively, were overexpressed in the 4T1.2 mouse model of breast carcinoma. Overexpression of wild-type CXCL12 potently inhibited both primary tumour growth and metastasis in this model. This was attributed to the induction of an anti-tumour response dependent, in part, on T cells, interferon-g and the cytotoxic mediators perforin and TRAIL. This response was characterised by increased numbers of CD11c⁺ cells in the tumour-draining lymph nodes and enhanced cytolytic activity of lymph node-derived effector cells against tumour cells. Unexpectedly, CXCL12[subscript](P2G) inhibited metastasis of tumour cells to the lungs of tumour-bearing mice, without affecting primary tumour growth. Intravenous injection of tumour cells revealed that CXCL12[subscript](P2G) expression could block metastatic steps occurring post tumour cell escape from the primary tumour, though a role for CXCL12([subscript](P2G) at earlier metastatic steps could not be ruled out. Further work is needed to clarify the precise stages of metastasis at which CXCL12[subscript](P2G) exerts its effects. No obvious effects on primary breast tumour growth were observed when CXCL16 or CXCL16([subscript](9-220) were overexpressed in tumour cells. Interestingly, CXCL16[subscript](9-220) expression inhibited experimental metastasis but not spontaneous metastasis. The findings of this study begin to shed light on the roles of CXCL12 and CXCL16 in breast cancer progression and also highlight the potential therapeutic applications of CXCL12, CXCL16 and/or their antagonists in the treatment of breast cancer and breast cancer metastasis. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297662 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007
| Identifer | oai:union.ndltd.org:ADTP/284352 |
| Date | January 2007 |
| Creators | Hampton-Smith, Sharon |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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