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Dissertation
The role of fractalkine in the early stages of skeletal metastasis from prostate and breast cancer
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2010
DOI:
https://doi.org/10.17918/00008535
Abstract
Both prostate and breast cancers metastasize to the bone with high propensity. Skeletal metastases significantly reduce patients' quality of life and represent a common lethal complication of neoplastic disease. Currently, no preventive or curative treatments for metastasis are available. Therefore, the advent of novel, effective therapies to impede metastatic dissemination is highly needed. Chemokines are a class of small, chemotactic cytokines that have been strongly implicated in metastasis. Among this family of proteins is fractalkine (CX3CL1, FKN), a unique chemokine that exists not only in a soluble form but also as a membrane-anchored molecule. In its membrane-bound form, FKN has been shown to mediate adhesion of cells expressing its receptor, CX 3CR1. FKN also acts as a chemo-attractant when cleaved from the membrane into a soluble protein. This dissertation describes the role of FKN and CX3CR1 in skeletal metastases from prostate and breast cancer . Expression and regulation of FKN in the bone has not been previously described. Shown here are data identifying FKN in cultured bone cells and ex vivo human tissue and bone marrow. Also described is a previously unknown mechanism of FKN cleavage in bone cells, via androgen stimulation, which could be important in the extravasation of prostate cancer into the bone. Furthermore, a novel in vivo mouse model of early experimental metastasis is described here in which fluorescent human cancer cells inoculated in the blood circulation can be identified in bone in progression from single cells to macroscopic tumors. This in vivo model has provided evidence that extravasation occurs rapidly after arrival of cancer cells to the bone. Finally, critical experiments combining our model of metastasis with molecular and genetic manipulation of FKN or CX3CR1 demonstrate that this pair plays a significant role in adhesion of cancer cells to the bone marrow sinusoids as well as their extravasation into the bone stroma. Overall, data produced by this research project strongly implicate FKN and CX3CR1 in skeletal metastasis. The work presented in this dissertation represents solid evidence that FKN and CX3CR1 should be evaluated as potential therapeutic targets for the prevention of skeletal dissemination of prostate and breast cancers.
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Details
- Title
- The role of fractalkine in the early stages of skeletal metastasis from prostate and breast cancer
- Creators
- Whitney L. Jamieson
- Contributors
- Alessandro Fatatis (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 163 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Drexel University
- Other Identifier
- 991021888794504721