Kathryn D. Held, MD, PhD
Associate Professor of Radiation Oncology (Radiation Biology)
Harvard Medical School
Associate Radiation Biologist
Massachusetts General Hospital
As part of the Cellular & Molecular Radiation Oncology Laboratory, the Held Laboratory examines molecular mechanisms in cellular responses to localized oxidative stress. Reactive oxidizing species (ROS) are produced by many agents used in the treatment of cancer, e.g., ionizing radiation, photodynamic therapy and some chemotherapy drugs. ROS-mediated processes also play critical roles in tumor development by initiating and participating in signaling cascades that lead to mitogenesis and tumor promotion. On the other hand, ROS are also vital to some normal physiological processes. We are involved in a program including radiation biologists, photobiologists, photochemists, biophysicists, and engineers addressing the question of how reactive oxidizing species initiate a diverse array of intracellular responses and how they initiate and propagate signaling to other cells. Using time-lapse microscopy we have extended the studies of others to show that x-ray irradiated cells can undergo apoptosis either rapidly, generally after higher doses, or at a delayed time after one or more cell divisions, usually occurring after lower radiation doses. Using caspase inhibitors and substrates we are studying the pathways involved in the pre- and post-mitotic apoptosis, and in apoptosis initiated by nuclear versus non-nuclear energy deposition.
The later studies are in collaboration with Professor Kevin Prise in the UK, using the unique x-ray microbeam developed by that group. The aim of the studies is to gain information on how to modify the apoptotic responses for therapeutic benefit. Additionally, we have shown that creation of ROS by ionizing radiation or by photoactive agents plus light in whole cells as well as in non-nuclear regions of a cell can elicit various responses including DNA damage and apoptosis in unirradiated bystander cells nearby or sharing medium with the treated cells. We have shown that secondary ROS, created as part of the cells' response to the initial energy deposition, are involved in the intercellular communication.
We have undertaken studies to identify the ROS involved and elucidate details of the molecular signaling pathways. Collectively, our data suggest that oxidative stresses initiate multiple intercellular/multicellular signaling pathways that can be separated spatially and temporally, but interact in producing the overall responses. The increased understanding from these studies of molecular mechanisms of oxidative stress as it relates to cancer development and treatment could ultimately translate into improved methods to prevent or treat cancer.
Mechanisms for Induction of Bystander Responses by Heavy Ions and Energetic Protons
In space, astronauts are exposed to a complex and unique radiation environment that includes energetic protons and heavy charged particles. Little is known about the biological effects of these particles, and there is particular concern about possible cancer induction. During long-duration missions outside the earths protective magnetic field, the cumulative radiation doses from these particles could be appreciable, but the individual particle traversals though the cells of an astronauts body would be well separated in time and location. Under these low fluence conditions, "bystander responses" could be important. Bystander responses are biological changes that occur in unirradiated cells neighboring the cells actually traversed by the ionizing particles. These responses result from signals sent by the "hit" cells to the unirradiated cells; the exact nature of the signals is unclear.
In recent experiments at the NASA Space Radiation Laboratory at Brookhaven National Lab, we have demonstrated that bystander responses, in the form of DNA damage and decreased cell survival, occur in several types of normal human cells exposed to high-energy protons and iron ions. We have shown that the intercellular communication occurs rapidly after radiation traversal of the "hit" cells and reactive oxygen species are involved in the signaling.
Our studies are now investigating in more detail the nature of the damage that initiates the intercellular signaling, now the signals are transmitted, and how cells of varying types in tissues in 3D communicate these signals to each other. The studies will shed light on mechanisms of cancer induction and late tissue damage that are risks to astronauts from space radiation and provide insight into how to prevent such possible deleterious effects.
Kathryn D. Held, MD, PhD
Principal InvestigatorGroup Members