Our Science – Tsokos Website

Maria Tsokos, M.D.

Laboratory of Pathology Head, Pediatric Tumor Biology and Ultrastructural Pathology Section Senior Investigator Building 10 Room 2A10 Bethesda, MD 20892 Phone:   301-496-3159 Fax:   301-480-9197 E-Mail:   mtsokos@mail.nih.gov

Biography

Dr. Tsokos received her M.D. from the National University of Athens, Greece, where she also worked on her postdoctoral thesis. She completed her residency training in anatomic pathology at the Laboratory of Pathology, NCI, and received training in pediatric and ultrastructural pathology at the same institution. Dr. Tsokos was named chief of the Pediatric Tumor Biology and Ultrastructural Pathology Section in 1988. In 1987, she was elected professor of pathology, School of Health Sciences of Crete, Greece. Dr. Tsokos is associate editor of the Journal of Investigative Medicine and serves on the editorial board of Clinical Immunology.

Research

Programmed Cell Death in Solid Pediatric Tumors: The Fas/FasL Signaling Pathway

The Pediatric Tumor Biology and Ultrastructural Pathology Section provides diagnostic services in pediatric tumor pathology and electron microscopy and studies mechanisms of programmed cell death (apoptosis) in solid pediatric tumors. In recent years, specific translocations and oncogene patterns have emerged as markers of clinical significance in solid pediatric tumors. The section incorporates novel approaches such RT-PCR and in situ hybridization in the diagnosis and classification of these tumors and studies the significance of molecular markers in their biology and prognosis.

The goal of our research is to study signaling pathways of programmed cell death (apoptosis) in solid pediatric tumors, such as the Ewing's sarcoma family tumors (ESFT), neuroblastoma, and rhabdomyosarcoma. With presently available therapeutic approaches, the prognosis of recurrent pediatric sarcomas is dismal. It is important to identify novel agents or strategies that would eradicate chemotherapy-resistant tumor cells. We elected to study the mechanisms that control the machinery of programmed cell death, hoping to understand reasons for chemotherapy failures and ways to overcome them.

Two major apoptosis pathways have been described in mammalian cells: an 'extrinsic' (death receptor-mediated) and an 'intrinsic' (mitochondria-activated) pathway. Both pathways proceed through activation of caspases and are inhibited by specific sets of inhibitory proteins. The intrinsic pathway is involved in chemotherapy-induced apoptosis, whereas the receptor-mediated pathways are viewed upon as alternative novel targets for cancer treatment.

We have shown that ESFT and neuroblastoma cells develop resistance to receptor- and drug-mediated apoptosis either by downregulating apoptosis inducing molecules, such as caspases, or by upregulating inhibitory proteins, such as survivin and bcl-2. We have also found that the apoptosis inducing ligand TRAIL (Tumor necrosis factor-Related Apoptosis Inducing Ligand) is a potent apoptosis inducer in ESFT cells in vitro, but its potency depends on levels of survivin expression. These studies suggest that alternative treatments with apoptosis-inducing molecules may be possible in the near future for solid pediatric tumors. We are currently investigating mechanisms to regulate the expression of proteins that affect the transmission of the apoptotic signal, so that we can intensify drug- and TRAIL-induced apoptosis in solid pediatric tumors.

This page was last updated on 6/12/2008.