The ready availability of knockout mice, in which the effects of selectively switching off genes could be tested, helped to highlight the cancer-inflammation link. Coussens and her U.C.S.F. colleagues Douglas Hanahan and Zena Werb reported in 1999 that mice engineered with activated cancer genes but without mast cells (another type of innate immune cell) developed premalignant tissue that did not progress to full malignancy. In 2001 Jeffrey W. Pollard and his co-workers at the Albert Einstein College of Medicine described mice that were genetically engineered to be susceptible to breast cancer tumors but that produced precancerous tissue that did not turn fully malignant unless it enlisted the assistance of macrophages.
The altered picture does not completely overturn the old one. In fact, it reveals that the immune system functions as a double-edged sword. The network of molecules and cells, second in complexity only to the brain, remains a paradox: sometimes it promotes cancer; other times it hinders disease. Some types of innate immune cells, such as natural killer cells, can actually protect against tumor growth. Others may nurture a malignancy only when the microenvironment is “polarized” into an inflammatory state; when not, they may blot it out. Inflammation, moreover, produces tumors in many organs, but not all—and its link to blood-borne cancers is not well characterized.
When looking for culprits, researchers have often focused their microscopes on macrophages, which occupy a meaningful spot among the white blood cells in the tumor microenvironment. The macrophages are capable of killing tumor cells or sending out an alarm to T cells of the adaptive immune system that something is amiss. But work by Pollard and other researchers has detailed how macrophages are “reeducated” by cancer cells to do their bidding. They become factories for cytokines and growth factors that nurture tumor development.
Turning the macrophages into traitors begins when tumor cells send out help signals that attract cells that become macrophages once they reach the tumors. Inside the tumors, proliferating cells grow so quickly that they begin to die for lack of oxygen. A combination of hypoxia and messages from the tumor cells initiates a process whereby the newly arrived macrophages assume their bad-body identity as tumor promoters. Cancer biologists give the name tumor-associated macrophages to these mutineers that congregate in and around the tumor.
Biologists have now been able to follow the inflammation link down to the level of individual signaling molecules, providing harder evidence for a connection to carcinogenesis. For example, nuclear factor-kappa B (NF-KB) is a complex of proteins that acts as a master switch for turning inflammation genes on and for controlling cell death. As biological pathways go, NF-KB’s is world-famous, having been discovered and patented for use in drug development by scientific stars that include Nobelists David Baltimore and Phillip A. Sharp and having subsequently become the object of multimillion-dollar patent litigation.
In 2004 Yinon Ben-Neriah and Eli Pikarsky of the Hebrew University of Jerusalem and their colleagues reported that mice engineered to develop hepatitis (which can cause liver cancer) contracted precancerous lesions that did not progress to full malignancy when NF-KB was curtailed through a genetic alteration or when the proinflammatory TNF signaling molecule was shut off. In the latter group, a neutralizing antibody blocked TNF and prevented it from binding to a receptor on the premalignant liver cells; loss of the receptor prevented the TNF from triggering a molecular cascade that turns on the NF-KB master switch. Blocking NF-KB prompted the precancerous liver cells to initiate apoptosis, or programmed cell death. In a related finding that year, Michael Karin and his collaborators at the University of California, San Diego, found that inhibiting NF-KB in mice engineered to develop colitis, which can lead to colon cancer, also promoted apoptosis. And shutting down the pathway in inflammatory cells, such as macrophages, deterred tumor development as well.