Gynecology; Immune System; Neoplasms; Ovarian Neoplasms; Pregnancy Complications; Reproductive Medicine
Led by Gil Mor, MD, PhD, the Reproductive Immunology Unit conducts studies that characterize the interaction between the immune system and reproductive organs. The focus is on two main areas of research: Immunology of Implantation: Studies are designed to understand immunological factors controlling the normal development of the trophoblast and its interaction with immune cells present at the implantation site. Studies are designed to understand the interaction between cancer cells and immune cells. A major focus of these studies is to understand the control of apoptosis in cancer cells and develop new therapeutic approaches that may reverse chemoresistance. We have developed a new test for the early detection of ovarian cancer based on a panel of known serum proteins associated with cancer biology. Each protein marker is analyzed using a routine ELISA assay, and the results evaluated using a score system.
In addition, the Unit has identified a sub-group of ovarian cancer patients, based on the expression of MyD88, which are resistant to Paclitaxel. The cancer cells of these patients express high levels of cytokines and chemokines and educate immune cells to promote tumor growth, angiogenesis and metastasis. The Unit has an Ovarian Cancer Tissue Bank that contains approximately 800 tissue samples of the primary and metastatic ovarian cancers as well as tissue samples from normal ovaries. In addition, as part of the NCI Ovarian Cancer Early Detection Program, the facility has in storage ascites and serum samples from patients with ovarian cancer and healthy age matched controls.
Specialized Terms: Immunology of Gynecologic tumors; Immunology of Implantation; Ovarian Cancer Stem Cells
Extensive Research Description
1) Immunology of Implantation: Studies are designed to understand immunological factors controlling the normal development of the trophoblast and its interaction with immune cells present at the implantation site. Our studies have identified the expression of Toll Like Receptors in trophoblast cells. These receptors allow the placenta to recognize and respond to any microorganism that may endanger the well being of the fetus.
We evaluate the effect of viral and bacterial infection on fetal development based on the type of response originated at the placenta.
2) Ovarian Cancer Translational Research laboratory” The major limitations in the treatment of ovarian cancer are:
i) the lack of an early detection tumor marker, and
ii) the resistance to chemotherapeutic agents. Presently there is no commercially available test that is diagnostic for either early or advanced-stage epithelial ovarian cancer. The most commonly used test, CA125, identifies a group of cell surface glycoproteins which have uncertain biological behavior and very limited clinical utility for the detection of early stage disease (less than 47% accuracy). Chemotherapy in the treatment of cancer was introduced into the clinical practice more than fifty years ago. Although this form of therapy has been successful for the treatment of some forms of cancer, it has not been the case for the majority of epithelial cancers of the breast, colon, lung and ovary. In addition, the collateral damage to normal cells, systemic toxicity due to lack of specificity, rapid drug metabolism, and acquired drug resistance are important clinical problems that have not been solved.
The objective of the translational research program is to resolve these limitations by:
1) Developing new markers for early detection
2) Identifying markers that can predict chemoresponse
3) Characterizing new therapeutic strategies for ovarian cancer
Developing new markers: We have reported the characterization and validation of a new test for the early detection of ovarian cancer in high-risk patients. The test has been licensed to Labcorp and is now commercially available as OvaSure. Additional studies are on going to determine the value of the biomarkers to monitor recurrence.
New therapies: We have isolated and characterized the ovarian cancer stem cells, which may represent the origin of recurrence. We identified a unique microRNA profile that differentiates these cells. One of these microRNA, mir-199A, is a major regulator of the NFkB pathway, and could be use as a target and a marker for differentiation. In addition, we have identified a new compound, which targets ovarian cancer stem cells by inhibiting the mTOR pathway. Immunology of Reproduction
1. TLRs and trophoblast response
2. Role of Dendritic cells and implantation
3. Effect of viral infection on fetal development
4. Trophoblast immune regulatory function
5. Inflammation and implantation
1. Apoptosis and cancer
2. Role of MyD88 in tumor renewal
3. Ovarian cancer stem cells
4. mir199 and regulation of IKK beta
5. Twist-1 and cancer stem cells
6. Inflammation and cancer stem cells differentiation
- Racicot K, Cardenas I, Wünsche V, Aldo P, Guller S, Means RE, Romero R, Mor G (2013) Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol. 2013 Jul 15;191(2):934-41. doi: 10.4049/jimmuol.1300661. Epub Jun 10. PMID: 23752614
- Yin G, Alvero AB, Craveiro, V, Holmberg JC, Fu HH, Montagna MK, Yang Y, Chefetz I, Nuti, S, Rossi M, Silasi DA, Rutherford T, and Mor G. (2012) Constitutive Proteasomal Degradation of TWIST-1 in Epithelial Ovarian Cancer Stem Cells Impacts Differentiation and Metastatic Oncogen: 32(1):39-49. PMID: 22349827
- Cardenas I, Means RE, Aldo PB, Koga K, Lang SM, Booth C, Manzur A, Oyarzun E, Romero R, Mor G, (2010) Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor, J Immunol;185(2):1248-57. PMID: 20554966.
- Steffensen KD, Alvero AB, Yang Y, Waldstrom M, Hui P, Holmberg JC, Silasi DA, Jakobsen A, Rutherford T, Mor G (2011) Prevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer. J Oncol. 2011:620523
- Mor G, Yin G, Chefetz I, Yang Y, Alvero A (2011) Ovarian Cancer Stem Cells and Inflammation. Cancer Biol. Ther. April 15; 11(8):708-13.
- Song J, Sapi E, Brown W, Nilsen J, Tartaro K, Kacinski BM, Craft J, Naftolin F, Mor G, Roles of Fas and Fas ligand during mammary gland remodeling, Journal of Clinical Investigation, 106(10):1209-20, November 2000 Abstract
- Alvero AB, Fu HH, Holmberg J, Visintin I, Mor L, Marquina CC, Oidtman J, Silasi DA, Mor G. 2009 Stem-Like Ovarian Cancer Cells can serve as tumor vascular progenitors, Stem Cell: August 5 on line
- Alvero AB, Montagna MK, Chen R, Kim KH, Kyungjin K, Visintin I, Fu HH, Brown D, Mor G. 2009 NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway Cancer. 2009 May 26
- Koga K, Aldo PB, Mor G. (2009)Toll-like receptors and pregnancy: Trophoblast as modulators of the immune response. Journal of Obstetrics and Gynaecolologic Research. 35(2):191-202.
- Alvero, A., Chen, R., Fu,H. Montagna, M., Schwartz, PE., Rutherford, T., Silasi, DA., Steffensen, KD., Waldstrom, M., Visintin, I., and Mor, G. (2009) Molecular phenotyping of human ovarian cancer stem cells unravel the mechanisms for repair and chemo-resistance. Cell Cycle: 8: 158-166
- Plaks V., Birnberg, T, Berkutzki, T., Kalchenko, V., Mor, G, Dekel, N, Neeman, M and Jung, S. (2008) Uterine Dendritic cells are crucial for Decidua Formation during Embryo Implantation. Journal of Clinical Investigation. 118 (2): 3954-65