Because of the way solid tumors adapt the body's machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.
"In a sense, these therapies can make the tumor healthier," said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. "Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot."
Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of
Nature Reviews Cancer.
Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.
The review article concludes that blocking HIF1 would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.
As a part of this work, Dewhirst's team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor's oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.
"It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels," Dewhirst said. "Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this."
Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies. (View these movies at the
Nature Reviews Cancer site:
http://www.nature.com/nrc/journal/v8/n6/suppinfo/nrc2397.html )
The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor's ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.
For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. "For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you'd target HIF1," he explained. "Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing."
The Duke team has completed a phase I trial with a HIF1 inhibitor. "We are actively pursuing this clinically and will be moving this study into Phase 2," Dewhirst said. "We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases."
Source: Duke University Medical Center
Related stories:
FOXO factor promotes survival of oxygen-deprived cancer cells
Scientists report that an evolutionarily conserved transcription factor may have both positive and negative effects on the growth of tumors, depending on whether or not the tumor cells have enough oxygen. The research, published by Cell Press in the December 28th issue of
Molecular Cell, provides critical new information about how normal cells and cancer cells survive under stress.
Hormone links sleep, hunger and metabolism, researchers find
While investigating how the hormone orexin might control sleep and hunger, researchers at UT Southwestern Medical Center have discovered, to their surprise, that it activates a protein, HIF-1, long known to stimulate cancerous tumor growth.
Normalizing tumor vessels to improve cancer therapy
Chemotherapy drugs often never reach the tumors they're intended to treat, and radiation therapy is not always effective, because the blood vessels feeding the tumors are abnormal—"leaky and twisty" in the words of the late Judah Folkman, MD, founder of the Vascular Biology program at Children's Hospital Boston.
Drugs to inhibit blood vessel growth show promise in rat model of deadly brain tumor
In a landmark study, Medical College of Wisconsin researchers in Milwaukee report that drugs used to inhibit a specific fatty acid in rat brains with glioblastoma-like tumors not only reduced new blood vessel growth and tumor size dramatically, but also prolonged survival. The study is the featured cover story of the August, 2008
Journal of Cerebral Blood Flow & Metabolism.
Using live fish, new tool a sentinel for environmental contamination
Researchers have harnessed the sensitivity of days-old fish embryos to create a tool capable of detecting a range of harmful chemicals.
Researchers discover how tumor suppressor inhibits cell growth
Genes that inhibit the spontaneous development of cancer are called tumor suppressor genes. One of the major tumor suppressors is p53, a protein that acts in the cell nucleus to control the expression of other genes whose products can inhibit cell proliferation (increase in cell number) and cell growth (increase in cell size). Abnormal cell proliferation and growth are characteristics of cancer. Scientists previously knew which p53 target genes inhibit cell proliferation, but those required for inhibition of cell growth were unknown.
Nanoparticles + light = dead tumor cells
Medical physicists at the University of Virginia have created a novel way to kill tumor cells using nanoparticles and light. The technique, devised by Wensha Yang, an instructor in radiation oncology at the University of Virginia, and colleagues Ke Sheng, Paul W. Read, James M. Larner, and Brian P. Helmke, employs quantum dots. Quantum dots are semiconductor nanostructures, 25 billionths of a meter in diameter, which can confine electrons in three dimensions and emit light when exposed to ultraviolet radiation.
How cells die determines whether immune system mounts response
Every moment we live, cells in our bodies are dying. One type of cell death activates an immune response while another type doesn't. Now researchers at Washington University School of Medicine in St. Louis and St. Jude's Children's Research Hospital in Memphis have figured out how some dying cells signal the immune system. They say the finding eventually could have important implications in the treatment of autoimmune diseases and cancer.