As researchers are increasingly discovering, the non-cancerous components of a tumor can be just as important as the cancer cells. At the annual meeting of the American Society for Clinical Oncology in Chicago earlier this week, Harvard Medical School and Massachusetts General Hospital researcher Rakesh Jain received ASCO's Science of Oncology Award for his decades-long work on the tumor microenvironment. In his award lecture, Jain discussed why normalizing the tumor microenvironment could be important for treating solid tumors. The microenvironment is abnormal and contributes to malignancy, progression, metastasis, and resistance to therapy, he said. A tumor is a complex system, he added, and there are three components other than cancer cells that must be treated — the blood vessels feeding the tumor, the lymphatic vessels, and the extracellular matrix holding the tumor cells together.
Using a variety of imaging techniques, Jain and his colleagues have been able to observe tumors growing in live animals in real time. The blood vessels growing into a tumor become disorganized and abnormal. The resulting heterogeneous blood flow impedes uniform drug delivery to the tumor, and can lead to hypoxia, which induces further growth of cancer cells. Jain's hypothesis was that if the pro- and anti-angiogenic factors could be restored to balance, as they are in normal cells, the blood vessels could be brought back into a normal state. To that end, he said, treatments like anti-VEGF therapies meant to starve the tumor by cutting off its blood supply must be applied judiciously to restore balance — going too far in the other direction once again induces hypoxia and encourages tumor re-growth, which defeats the purpose.
Normalization of the blood vessels also resolves the paradox of how to deliver chemotherapy through the necessary blood vessels while killing off enough blood vessels to starve the tumor. In animal models, he added, this strategy worked. And clinical trials have shown that patients with normalized vasculatures survive longer. This indicates that the dose of anti-VEGF therapy matters a great deal, Jain said.
Jain also discussed lymphatic vessels, which are crushed in a tumor by all the cells crowding around them, and won't allow drainage of excess fluid. Various techniques to restore these vessels have shown that they are vital to reducing fluid pressure inside the tumor. And finally the cancer cell matrix — which is made of collagen fibers that impede the flow of cancer drugs — must also be addressed, he said. Studies have shown that anti-hypertensive drugs loosen the stiff collagen, allowing chemotherapeutic agents to flow to all parts of the tumor.