Hypoxic Environment May Lead to Tumor Resistance

PALO ALTO, Calif--New research into the nature of malignant cellsdeep within the interior of solid tumors suggests a possible explanationas to why tumors with large hypoxic areas tend to be aggressiveand treatment resistant.

The research team, led by Dr. Amato J. Giaccia of Stanford University,studied the central area of tumors where the blood supply is poor,causing hypoxia. Their work in a murine model showed that thehypoxic state stimulates production of the p53 protein, whichcan block cell proliferation or lead to cell self-destruction.

While large numbers of malignant cells in the tumor interior diein this way, some tumor cells in the hypoxic environment acquirea p53 gene mutation that prevents their destruction and allowsthem to survive with little oxygen, giving them a distinct competitiveadvantage in the hypoxic environment over cells that lack thegene defect, Dr. Giaccia says (Nature, January 4, 1996).

Such tumor cells may be resistant to chemotherapy and radiation,since, thanks to the p53 mutation, they are no longer affectedby the treatment-induced DNA damage that stimulates productionof p53, says Dr. Giaccia and his colleagues at Stanford, MIT,the University of Pennsylvania, and Cold Spring Harbor Laboratory.These resistant cells can eventually take over the entire tumor,producing an aggressive malignancy that is resistant from thetime of diagnosis.