All ETDs from UAB

Advisory Committee Chair

David T Curiel

Advisory Committee Members

Maaike Everts

Zdenek Hel

John D Mountz

Selvarangan Ponnazhagan

Theresa V Strong

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cancer metastasis is a multi-step process, and different cancer cells metastasize to different organs. The process includes proliferation and angiogenesis of the primary tumor, detachment of the primary tumor and invasion of the tumor into the lymphatics and capillaries, with embolization of the tumor cells to distant organs. The tumor cells then undergo arrest followed by extravasation with establishment of the tumor microenvironment and proliferation/angiogenesis of tumor cells to develop metastatic clones. However, evidence of metastasis is almost always associated with a poor prognosis. Multiple treatment modalities are being evaluated for cancer metastasis targeting one or more of the aforementioned steps. Chemokines expressed in different tissues have been shown to attract and cause the proliferation of cancer cells expressing the corresponding chemokine receptors, thereby establishing metastasis in that tissue. The `CXC' family chemokine ligand 12 (CXCL12) and 'CXC' receptor 4 (CXCR4) constitute one such chemokine/chemokine receptor interaction that has been shown to cause tumor metastasis to lung. Different treatment approaches targeting CXCR4 are being investigated with varying degrees of success. Here, we report a novel proof-of-concept approach to targeting and functionally decreasing CXCL12 and thereby decreasing the metastasis of cancer cells to the lung. We utilized an adenoviral vector (Ad) to deliver a soluble CXCL12 binding domain of CXCR4 (sCXCR4) to functionally decrease CXCL12 in a B16F10 mouse melanoma model of pulmonary metastasis to validate our hypothesis. Our results showed that sCXCR4 decreased the metastatic burden of tumor cells in the lungs. Our proof-of-concept results demonstrate a different anti-metastatic gene therapy approach that could have broad and exciting clinical translational implications.

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