A basic distinction in the conceptualization of cancer is between primary tumors and metastases. But in the August 2006 issue of Nature Medicine, two researchers argued that the primary tumor may be more like a metastasis than is currently recognized. They argued that even what oncologists now would consider a primary tumor may in fact be a collection of small growths, and that this fact may be part of what makes cancer so dangerous.

"The perfect analogy is a weed," author Larry Norton, chair of clinical oncology at New York City's Memorial Sloan-Kettering Cancer Center in New York City, told BioWorld Today. "Weeds are not dangerous because they are big. And weeds are not particularly fast-growing plants." Instead, "weeds are dangerous because they seed."

Although frustrated gardeners might say weeds are indeed fast-growing, the idea that even a primary tumor might be made of many small cell masses, rather than one large one, can explain several features of cancer.

The question of whether a primary tumor is made up of one growth of 1 million cells or 10 growths of 100,000 each is not an academic one. Instead, each scenario implies different things about how such a mass would grow. This is because biological growth usually happens at the edge or surface of a structure. And "if you have a mass and the growth is happening on the outside, that itself will give a plateau of growth," Norton explained.

Small tumors, though, have more surface area relative to their volume than large ones; so 10 small tumors will have more surface area relative to their volume than one large one. In practice, that means that tumors might grow not just because their cell division processes are unregulated - which they obviously are. But Norton argues that additionally, the rapid growth and high cell density of tumors might be "the cells' normal response to the 'start-up' nature of the small tumor seedlings comprising the malignant conglomerate."

Amato Giaccia, professor of cancer and radiation biology at Stanford University School of Medicine in Palo Alto, Calif., told BioWorld Today that he believes "there is some validity to the concept" that processes like seeding and migration, in addition to proliferation, must play a role in primary tumor growth. Giaccia and his colleagues at Stanford, the University of Leipzig and South San Francisco-based Fibrogen Inc. published data in the June 1, 2006, issue of Cancer Research showing that an antibody to connective tissue growth factor, or CTGF, blocked both tumor growth and metastases of pancreatic cancer in mice.

Though it is not unique, Amato called the fact that the antibody worked on both primary tumors and metastases "somewhat unusual." Interestingly enough, Norton's Nature Medicine article suggested that cancers with "intense self-seeding powers" might never form discrete primary tumors, "but rather demonstrate a diffuse infiltration of the organ of origin." Norton uses pancreatic cancer as an example of this type of growth, which would be expected to be associated with strong metastatic behavior.

The exact mechanisms by which blocking connective tissue growth factor is useful to prevent tumor growth and metastases is still unclear, and under active investigation by Giaccia and his team. Giaccia declined to speculate on mechanisms, but did point out that CTGF is involved in regulating survival, proliferation, angiogenesis and cell adhesion - "so you've got four major mechanisms that it could be affecting right there."

Giaccia's group and their Leipzig colleagues also recently published data in Nature showing that inhibition of the enzyme lysyl oxidase prevented breast cancer metastases in mice, while in patients, high expression levels of lysyl oxidase correlated with more metastases and poor survival. Giaccia noted that blocking lysyl oxidase works by, among other things, inhibiting cell movement, "so that would support [Norton's] theory."

From a drug development standpoint, though, Giaccia suggested that focusing on the nature of the primary tumor is not the most pressing approach: "We have a lot of ways to control primary tumors, but we fail to control metastatic disease," he said.

Norton, however, seems a bit more skeptical of the idea that primary tumors can be well-controlled; in their Nature Medicine article, Norton and co-author Joan Massague called the current therapeutic regimens "largely disappointing" and noted that "because of our community's historic focus on cell proliferation as the core aberrancy in cancer, almost all anticancer drugs now in common use were developed as antiproliferative interventions." He continued that the "drugs have unquestionably proved useful," a cure for "epithelial cancers is uncommon, however, and even the advances we have made in the use of postsurgical adjuvant drug therapy may reflect time delays (as regrowth proceeds from residual cells) rather than eradication of all cells in some individuals with cancer."