Current Research Focus
The Radiation and Cancer Biology Section is under the direction of Marc Mendonca, Ph.D.
In my lab we are working on the cellular and molecular basis of radiation-induced carcinogenesis in human cells. Our long-term goal is to understand radiation-induced secondary cancers in patients who have successfully undergone treatment for their primary malignancy. We hope to use this knowledge to develop or test better ways to prevent or delay the appearance of these secondary cancers. In addition, this work has relevance for understanding radiation-induced cancers and their prevention in populations which have been exposed occupationally or accidentally to substantial doses of ionizing radiation such as X-rays, gamma-rays, or even the high energy charged particles which high altitude pilots and astronauts are exposed to during their flights.
Specifically, we are investigating the roles of genomic instability, tumor suppressor gene deletion, loss of apoptotic regulation, and epigenetics in the radiation-induced neoplastic transformation process. Our work suggests that the delayed appearance of radiation-induced neoplastic cells correlates with the expression of delayed death caused by the onset of apoptosis over 8 days or 10 cell divisions after radiation exposure. We propose that radiation-induced neoplastic transformation of HeLa X fibroblast hybrid cells is a consequence of long-term genomic instability that leads to cell death in a large percentage of the progeny of irradiated cells, but also to neoplastic transformation in a small percentage of cells due to loss of tumor-suppressor function and overexpression of prosurvival BCL gene family members. By cytogenetic and deletion analysis of radiation-induced tumorigenic cell lines called GIMs we have identified two novel tumor suppressor loci for the HeLax fibroblast hyrid cells at chromosome 11q13 and also on chromosome 14. Work from our collaborators has confirmed the involvement of the 11q13 tumor suppressor locus in primary cervical cancer. We are currently identifying candidate genes at the 11q13 locus, and will be investigating their involvement and potential mechanism of action.
My laboratory is also part of a recently funded DOD program project that is testing the efficacy of various gene therapy strategies to increase the in vivo radiation and chemo-sensitivity of ovarian cancer. For this study we are collaborating with four other laboratories at IU School of Medicine and at IU Bloomington to specifically interfere with human ovarian cancer DNA repair capacity and cell cycle progression, thereby increasing tumor kill.
In our laboratory, we are attempting to elucidate the mechanisms of radiation-induced and heat-induced cell killing. We are also interested in determining how hyperthermia sensitizes mammalian cells to ionizing radiation. A better understanding of the biological mechanisms of interaction of hyperthermia with radiation damage should lead to refinement in its clinical implementation.
Much of our attention has been focused on identifying the role of the nuclear matrix in the radiation and heat-shock response during DNA repair, and programmed cell death (apoptosis) of cultured mammalian cells. Data from our laboratory and others strongly indicate that the nuclear matrix--the protein network that gives the nucleus its structure and regulates DNA and RNA synthesis--is a target of cell killing. Changes in nuclear matrix protein composition and alterations in structure which we have observed in heated or irradiated cells are likely to be detrimental to the many important cellular processes that are associated with that structure.
Heat-radiosensitization is believed to be mediated by an inhibition of repair of radiation-induced double strand breaks (DSBs) by heat. We recently accumulated exciting preliminary evidence that indicates that hyperthermia induces both aggregation and translocation from the nucleus to the cytoplasm of specific critical proteins believed to be involved in the repair of radiation-induced DSBs. Such alterations or redistribution of these proteins might be expected to result in a decrease in DSB repair efficiency, and may be implicated, at least in part, as a mechanism for heat-radiosensitization. Experiments are underway in our laboratory that will hopefully allow us to gain further insight into the mechanisms by which heat inhibits DSB repair and potentiates radiation-induced cell killing.
Other interests of a more translational nature include the development of assays for predicting radiation sensitivity of radiation therapy and diagnostic radiology patients, radiation cataractogenesis, and the identification of agents that act as radiosensitizers or radioprotectors.