Boston--February 2004, Harvard Medical School affiliate Beth Israel Deaconess Medical Center--Many people have tiny tumors, but the vast majority of these are pinhead in size, dormant, undetected, and never develop into true, life-threatening cancers, write cancer researchers Judah Folkman, MD, of Children's Hospital Boston, and Raghu Kalluri, PhD, of Beth Israel Deaconess Medical Center.
In an essay in the Feb. 26 issue of Nature, Folkman and Kalluri suggest that most tumors don't develop a blood supply that would allow them to grow and progress to cancer, because people produce natural inhibitors of blood vessel growth, or angiogenesis. They write that a better understanding of these inhibitors may yield a new generation of nontoxic anticancer drugs that could be given preventively to people at high risk for developing the disease.
The essay, titled "Cancer without Disease," cites autopsy studies which have revealed that more than a third of women aged 40 to 50 have small in situ breast carcinomas, whereas only 1 percent are diagnosed with clinical breast cancer. Analagous findings hold for prostate cancer in men. Similarly, autopsies show that virtually all people aged 50 to 70 have small in situ thyroid tumors, yet well below 1 percent are diagnosed with clinical thyroid cancer.
"We may have to define cancer as having two critical phases," Folkman and Kalluri write. In the first phase, which isn't inherently lethal, genetic mutations develop that transform normal cells in the body into cancerous cells. The second phase involves what Folkman and colleague Douglas Hanahan at UCLA termed the "angiogenic switch" in Cell in 1996, in which growth factors secreted by a tumor to attract a blood supply overcome the defense provided by natural angiogenesis inhibitors.
But many small cancers never reach this second phase. For example, people with Down syndrome rarely develop solid tumors. It's thought that their extra copy of chromosome 21 endows them with elevated levels of endostatin, a natural angiogenesis inhibitor.
Inspired by such examples, a major current focus of Folkman's Vascular Biology Program at Children's Hospital Boston is on predicting the "angiogenic switch" and delaying or preventing it with natural angiogenesis inhibitors. Preventive therapy could be offered to people with a genetically increased risk for cancer (such as women carrying the BRCA1 gene), people with a family history of cancer, and people whose cancer has been treated but are at risk for recurrence. Eventually, Folkman says, it may be possible to treat patients with angiogenesis inhibitors before a tumor can even be visualized by radiologists and then monitor the results with additional urine or blood tests.
At BIDMC, says Kalluri, "Our lab is currently testing whether a disruption of the 'angiogenic checkpoint,' caused by either an increase in angiogenic factors such as VEGF or a decrease in angiogenic inhibitors such as thrombospondin-1 or tumstatin, could represent a lethal step in the progression of cancer. Consequently, we are investigating whether genetic control of the physiological levels of endogenous inhibitors might represent a critical line of defense against the development of malignancies."