Khazali, Ahmad Suhail
(2017)
THE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN TUMOR METASTASIS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Metastasis is often a deadly disease but highly inefficient as it involves several complex sequential processes such as invasion, hematogenous dissemination and distant organ colonization. Tumor suppressor E-cadherin, which is the key biomarker for epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), plays essential roles in cancer invasion and colonization. Organ colonization has been proposed to be the rate-limiting step of metastasis as most cancer cells undergo apoptosis in these restrictive foreign microenvironments. However, some metastatic cells manage to evade apoptosis by undergoing cellular quiescence and later grow out to form deadly overt metastases.
Herein, we investigated the roles of chemokines and chemokine receptors in mediating tumor phenotypic transition during cancer invasion and tumor escape from dormancy during liver colonization. Chemokine receptor CXCR3 mediates immune cell chemotaxis but inhibits adherent cell locomotion. These opposing effects on cellular motility are accomplished via two CXCR3 isoforms. We hypothesized that the anti-migratory isoform CXCR3B promoted Ecadherin expression to allow cancer cell seeding. CXCR3B overexpression induced E-cadherin expression and CXCR3B-knockdown reduced total and membranous E-cadherin. We also found that the correlation between CXCR3B and E-cadherin expression was significantly conserved in human prostate cancer liver metastasis in mice.
Next, we utilized in vitro and ex vivo co-culture systems to uncover the soluble factors that mediate tumor emergence from dormancy. In vitro co-culture with hepatic stellate cells (HSCs) significantly elevated tumor growth. Protein analyses of primary liver non-parenchymal cells and immortalized HSCs revealed increased secretion of pro-inflammatory chemokines IL-8 and MCP-1. We further noted that IL-8, not MCP-1, directly augmented cancer cell growth and mediated tumor escape from dormancy, potentially through ERK activation.
In summary, we establish novel functions for CXCR3 and IL-8 during tumor metastasis. CXCR3B can induce E-cadherin re-expression that may facilitate cancer cell seeding and protect the cells from drug-induced apoptosis. HSC-derived pro-inflammatory chemokine IL-8 can drive tumor escape from dormancy in the liver. These findings may have substantial implications on the management and treatment of metastatic disease. Targeting IL-8 or inflammation in general, may prove beneficial to curb cancer outgrowth at this rate-limiting step of metastasis.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Khazali, Ahmad Suhail | ahk28@pitt.edu | ahk28 | |
|
| ETD Committee: |
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| Date: |
12 October 2017 |
| Date Type: |
Publication |
| Defense Date: |
17 July 2017 |
| Approval Date: |
12 October 2017 |
| Submission Date: |
10 October 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
179 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
EMT, MET, E-cadherin, CXCR3, IL-8, MCP-1, hepatic stellate cells, dormancy, emergence |
| Date Deposited: |
12 Oct 2017 13:56 |
| Last Modified: |
12 Oct 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33251 |
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