“Expression of human beta-defensin-2 in intratumoral vascular endothelium and in endothelial cells induced by transforming growth factor beta”
Peptides 2010 Feb
Kawsar HI, Ghosh SK, Hirsch SA, Koon HB, Weinberg A, Jin G.
Human beta-defensin-2 (hBD-2) is a small cationic peptide originally identified from psoriatic skin lesions as an antimicrobial agent of the innate immune system. The expression of hBD-2 is believed to be induced exclusively in epithelial cells by microbial components and certain proinflammatory cytokines, such as interleukin-1 beta (IL-1 beta). In this study, we report, for the first time, that hBD-2 is expressed in vascular endothelial cells associated with oral squamous cell carcinoma (OSCC) and Kaposi’s sarcoma lesions, but not in that of normal stroma. Expression of hBD-2 in vascular endothelial cells was further substantiated by in vitro experiments using cultured human umbilical vein endothelial cells (HUVECs). Transforming growth factor beta1 (TGF beta 1) and IL-1 beta, two well-known tumorigenic inflammatory mediators, induce hBD-2 transcript and peptide expression in HUVECs. However, TGF beta 1 does not stimulate hBD-2 expression in oral epithelial cells. In addition, proinflammatory cytokines and microbial reagents do not induce the expression of hBD-1 and hBD-3 in HUVECs. Since hBD-2 has been shown to modulate migration, proliferation, and tube formation of HUVECs in vitro and participate in immune cell trafficking, its expression in vascular endothelial cells located within malignant lesions may play a role in tumor angiogenesis and cancer metastasis.
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Use of chemotherapeutic agents to induce cytotoxic DNA damage and programmed cell death is a key strategy in cancer treatments. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway resulted in formation of abasic or apurinic/apyrimidinic (AP) sites, and blockage of AP sites led to a significant enhancement of drug sensitivity due to reduction of DNA base excision repair. Since a number of chemotherapeutic agents also induce formation of AP sites, monitoring of these sites as a clinical correlate of drug effect will provide a useful tool in the development of DNA-targeted chemotherapies aimed at blocking abasic sites from repair. Here we report an imaging technique based on positron emission tomography (PET) that allows for direct quantification of AP sites in vivo. For this purpose, positron-emitting carbon-11 has been incorporated into methoxyamine ([(11)C]MX) that binds covalently to AP sites with high specificity. The binding specificity of [(11)C]MX for AP sites was demonstrated by in vivo blocking experiments. Using [(11)C]MX as a radiotracer, animal PET studies have been conducted in melanoma and glioma xenografts for quantification of AP sites. Following induction of AP sites by temozolomide, both tumor models showed significant increase of [(11)C]MX uptake in tumor regions in terms of radioactivity concentration as a function of time, which correlates well with conventional aldehyde reactive probe (ARP)-based bioassays for AP sites.
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Colon cancer is the second most deadly cancer in the U.S. despite being the most preventable. The American Gastroenterological Association (AGA) recently announced concern that people will neglect colon cancer screening during this economic climate.
Screening is recommended in both sexes over age 50 and earlier if a patient has a family history of this disease. However, some people put it off due to fear of having a colonoscopy, which can be both invasive and expensive. As more people lose health insurance coverage, the high cost of this procedure may lead many more people to forego screening.
Sanford Markowitz, MD, CWRUmedicine oncologist and colon cancer researcher of the University Hospitals Ireland Cancer Center at University Hospitals Case Medical Center, has developed a less expensive, non-invasive test for this disease.
About the test:
- The non-invasive test detects DNA markers for colon cancer using a stool sample that is taken at home
- The DNA Stool Test is available now at the doctor’s office, or can be easily ordered by the doctor
- Although the test isn’t covered by insurance, the cost is significantly lower
- Patients with negative results will not need to commit time and money to having a colonoscopy; patients with positive results will move forward with colonoscopy to provide more information
- It is 80 percent effective and while colonoscopy is still the most effective test, it is not useful if patients are avoiding it altogether
- The American Cancer Society added the test to its screening guidelines last year
Learn more at CWRUmedicine.org