How does cancer spread? Scientists at Emory's Winship Cancer Center have identified a crucial step in the mechanism driving the migration of cancer cells, via blood vessels or the lymphatic system, from their primary tumor to secondary sites in the body. Controlling the spread, or metastasis, of malignant tumors is an enormous challenge facing cancer patients and oncologists, particularly in virulent cancers often found in the colon, lung, breast, liver and kidney.
The research, conducted by John Petros, assistant professor of surgery/urology, is reported in the February issue of Genes, Chromosomes and Cancer. In his study on renal cell carcinoma, the most common adult malignancy of the kidney, Petros discovered an abnormality in the gene called ND1. In the gene, which encodes for proteins, he found a deletion that renders it significantly shorter than normal.
The deletion cripples the cancer cell, preventing its detachment from the tissue in which it is anchored. In looking at 39 renal cell carcinomas, Petros found one primary tumor that expressed the ND1 gene deletion. The deletion was not present in any of that tumor's metastases, nor in any unaffected tissues, including the surrounding normal kidney, liver, heart and muscle. "This implies that the tumor cells containing the ND1 deletion are not competent to metastasize," Petros said, "and that the functions performed by a healthy ND1 gene may be a prerequisite for metastasis."
The ND1 gene is located on the strands of DNA in the mitochondria, the tiny "powerhouse" inside the cell. Each cell contains about 100 to several thousand mitochondria, which can independently replicate because they have their own DNA, separate from the more complex DNA in the cell's nucleus. The function of mitochondria is to transform food molecules into usable energy, or ATP.
The ND1 gene is involved in the part of this complex metabolic process called oxidative phosphorylation. When ATP cannot be produced efficiently because of a glitch in the oxidative process, increased numbers of cell-damaging oxygen-free radicals are released. These free radicals can in turn interact with both mitochondrial and nuclear DNA, causing even further mutation. In normal, non-cancerous tissue, DNA mutation is damaging and undesirable. In a tumor cell, however, Petros' work shows that paradoxically, this cycle may inhibit metastasis. If this is so, scientists would search for a way to disrupt ND1 function only in a patient's tumor cells to stop potentially roving tumor cells in their tracks, and leave healthy cells with a full-length, intact ND1 gene for efficient energy production.
Petros' discovery is the first reported case of a deletion within a gene found in tumor mitochondrial DNA. It has far-reaching implications, because the facility with which a cell generates ATP is a pivotal element in the theories of why we age and how we develop cancer.
The next step is to create a laboratory model to further study the effects of mutant mitochondria. Petros will start with a cancer cell line that has a well-known rate of metastasis. Using cell fusion techniques, he will create a new cell line that substitutes the ND1 deletion for the healthy gene, and see if it slows metastasis.
"This provides a fertile area for future investigations, " said Petros. "If the mechanism of metastasis could be mapped out, we could then define ways of inhibiting it."
-- Kate Egan