Journal of oncobiomarkers最新文献

Kaposi's sarcoma (KS), a common cancer in individuals with HIV/AIDS, lacks a curative therapy. Few studies have examined changes in extracellular matrix (ECM) protein profiles in the development of KS. Here we used an in vitro (human dermal microvascular endothelial cells, DMVEC) and an in vivo mECK mouse model of Kaposi's to study the impact of infection on tropoelastin. Using DMVEC, Kaposi's sarcoma-associated herpesvirus (KSHV) reduced tropoelastin transcription when examined at 2, 5, 7, and 10 days post addition, a finding that was inversely correlated with a rise in viral latency associated nuclear antigen (LANA) transcription. Immunohistochemical/immunofluorescence data confirmed that DMVEC cells were KSHV-infected (evidenced by LANA production) and that there was a loss of tropoelastin protein compared to controls. Using the mECK36 mouse model of KS we observed a reduced expression of tropoelastin mRNA in 3 of 3 tumor biopsies compared to controls. Immunofluorescence staining showed high levels of viral LANA expression in the tumor core, while immunohistochemical staining showed high levels of LANA expression and spindle cells in tumors. Dual label immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue revealed reduced expression of tropoelastin in LANA positive spindle cell regions quantified by Ariol SL-50 scanning analysis. Together, this suggests that alterations in tropoelastin may play an important role in the development of Kaposi's and could serve as an early marker of this disease. This information will also allow us to explore the potential role of tropoelastin anti angiogenic properties in an in vivo model for KS disease.

mTOR is a serine/threonine kinase and plays a critical role in mammalian cell growth, survival, and metabolism. mTOR is present in two cellular complexes: mTORC1 and mTORC2. Dysregulation of the mTOR pathway has been related to tumorigenesis, poor prognosis and/or chemotherapy resistance in a variety of malignancies. Inhibition of mTORC1 by Rapamycin and its analogs has been explored to treat a number of tumors. However, the effectiveness of patient response is limited and not all patients respond. Second generation of mTOR inhibitors have recently been developed to target mTOR kinase activity and to suppress both mTORC1 and mTORC2. Dual mTORC1/mTORC2 inhibitors generally are more efficacious in preclinical studies and clinical trials. We and others have recently found that dual mTORC1/mTORC2 inhibitors sensitize T-cell acute lymphocytic leukemia and rhabdomyosarcoma cells to DNA damaging agents by suppression of expression of FANCD2 of the Fanconi anemia pathway, an important DNA repair mechanism that is associated with drug resistance of multiple types of cancer. This review will highlight mTOR and the Fanconi anemia pathway in cancer, with a particular attention to our newly discovered connection between mTOR and the Fanconi anemia pathway.

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. There is a clear molecular link between cyclooxygenase-2 (COX-2)-derived prostaglandin E₂ (PGE₂) production and CRC progression. Although selective COX-2 inhibitors as well as non-steroidal anti-inflammatory drugs (NSAIDs) reduce the number and sizes of colonic adenomas, increased cardiovascular risks of selective COX-2 inhibitors and increased gastrointestinal side-effects of NSAIDs limit their use in chemoprevention of CRC. Glucocorticoids induce apoptosis and are endogenous, potent COX-2 inhibitors. Glucocorticoids have been used for the treatment of hematologic malignancies, but not for solid tumors due to adverse side-effects such as immunosuppression and osteoporosis. In tissues, glucocorticoid actions are down-regulated by t y p e 2 1 1 β-hydroxysteroid dehydrogenase (11βHSD2), and inhibition of 11βHSD2 activity will elevate intracellular active glucocorticoid to levels that effectively suppress COX-2 expression. Both COX-2 and 11βHSD2 increase in Apc^+/min mouse intestinal adenomas and human colonic adenomas and either pharmacologic or genetic 11βHSD2 inhibition leads to decreases in COX-2-mediated PGE₂ production in tumors and prevents adenoma formation, tumor growth, and metastasis. 11βHSD2 inhibition may represent a novel approach for CRC chemoprevention by increasing tumor cell intracellular glucocorticoid activity, which in turn inhibits tumor growth by suppressing the COX-2-derived PGE₂ pathway, as well as other pathways, without potential side-effects relating to chronic application of COX-2 inhibitors, NSAIDs and glucocorticoids.