Regulatory roles of endothelial cells in cancer

This thesis describes the biochemical regulatory impact of endothelial cells, the cells that line all blood vessels, in cancer. Our work draws from concepts in vascular repair and tissue engineering and extends the view of tumor vessels from perfusing tubes to delivery platforms lined with potent paracrine regulatory cells. We focus on how the endothelial cells themselves regulate tumor biology in a state-dependent fashion. We found that healthy endothelial cells inhibit cancer cell proliferation, invasiveness, and inflammatory signaling and that a defined perturbation of the healthy endothelial cell state - silencing of the gene encoding perlecan - causes loss of the invasion-inhibitory capabilities of endothelial cells by transcriptional upregulation of IL-6. The use of matrixembedded endothelial implants enabled the effects in cell culture to be expanded and validated in animal models. Moreover, endothelial cells exposed to a pathologically activating and inflammatory culture environment, similar to endothelial cells exposed to the atherosclerotic milieu, were leaky and inflamed, with dysregulated proliferative and leukocyte binding properties. Unlike healthy endothelial cells, which suppress cancer cell proliferation and metastasis, these dysfunctional endothelial cells instead aggressively stimulated cancer cell inflammatory signaling and invasiveness, which correlated with stimulation of spontaneous metastasis when implanted as matrixembedded cell implants adjacent to tumors. Fascinatingly we were able to identify markers of endothelial dysfunction, including reduction of endothelial perlecan expression, in human non-small cell lung carcinoma specimens. The state-dependent impact of endothelial cells on cancer biology adds another element to stromal regulation of cancer and brings together a range of disciplines and disparate findings regarding vascular control of tumors. That healthy endothelial cells suppress and dysfunctional cells promote tumor aggression may help to explain undesired effects of therapies that target tumor blood vessels. The harnessing of tissue engineering to regulate vascular and cancer biology may motivate the development of innovative pharmacologic and cell-based therapies for cancer.

Department dc:contributor.department

Harvard University--MIT Division of Health Sciences and Technology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2011

Author dc:creator

• Franses, Joseph W. (Joseph Wang)

Advisor dc:contributor.advisor

• Elazer R. Edelman.

• Harvard University--MIT Division of Health Sciences and Technology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/65518

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/65518