A new view of cancer pg. 4
When the macrophages reach the site of the tumor, they squeeze through the blood vessel lining into the underlying tissue. Normally, they would sound the alarm, calling other elements of the immune system to attack the tumor. Instead, they are “re-educated” by the tumor to produce a variety of factors that nourish the tumor and enable it to break through the connective tissue that restrains it.
These “tumor-associated macrophages,” as they are called, also can release immunosuppressive factors—various members of the interleukin family of cytokines—that blunt the ability of the body’s immune surveillance system to detect and attack the tumor. So can other white blood cells (lymphocytes) that infiltrate tumors.
One possible way to stop this process and prevent tumor progression is to block expression of chemokines that chronically recruit inflammatory cells to the site where the tumor is developing, suggests Ann Richmond, Ph.D., Ingram Professor of Cancer Research at Vanderbilt. Richmond is co-discoverer of one of the first chemokines that has been shown to affect melanoma tumor growth.
In 2001, Pollard and his colleagues at the Albert Einstein Cancer Center reported that colony stimulating factor-1 (CSF-1), a major macrophage growth factor and chemokine, seemed to be essential in a mouse model of breast cancer for “metastasis,” spread of a tumor from its site of origin to other parts of the body.
Mice that lacked the gene for CSF-1 still developed mammary tumors, but the spread of the metastatic tumors to the lungs was significantly delayed. In addition, these tumors did not have the normal infiltration of macrophages seen in mice with the normal CSF-1 gene. When the gene was reintroduced into the mice, metastasis—in conjunction with macrophage infiltration—was restored. “At least in this model,” Pollard explains, “macrophages are bad news.”
Macrophages are not the only cell type that can fan the inflammatory flames of cancer. Zena Werb, Ph.D., Lisa Coussens, Ph.D., and their colleagues at the University of California, San Francisco have found that cells in the connective tissue surrounding the tumor also can send out signals that help it grow and spread. The cells “talk” to each other, just as they do during development of mammary glands or hair follicles. “The environmental side and the tumor side co-evolve,” explains Werb, professor and vice chair of Anatomy at UCSF.
Most cancers arise from the epithelium, the layer of cells that separate underlying tissues from the outside world. The epidermis of the skin, the linings of the lungs and digestive tract—all are examples of epithelial tissues. Underneath is the stroma, which provides the connective tissue, blood vessels, nerves and other vital physiological functions. Between cells is the extracellular matrix, which plays a role in tissue development and healing. It is here that the cells travel on their fibrous “superhighways” from one location to another.