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"These are some very extraordinary laboratories that are participating," says Suresh Mohla, Ph.D., chief of the Tumor Biology and Metastasis Branch in the NCI Division of Cancer Biology and program director for the TMEN. "They're working on human cancers that range from breast to colon to glioblastoma, and other cancer sites as well, and they bring state-of-the-art technologies to the network. We are very pleased."
Fertile ground
The idea that the microenvironment plays an important role in a cancer's progression is not new.
In the late 19th century, Stephen Paget, assistant surgeon to the West London Hospital and the Metropolitan Hospital, proposed the now famous "seed and soil" hypothesis of metastasis.
"When a plant goes to seed," he wrote in an 1889 paper in The Lancet, "its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil."
Paget was trying to understand the distribution of metastases in breast cancer – if all organs were equally receptive, he reasoned, then secondary tumors should be randomly distributed. But his examination of 735 case histories of fatal breast cancer revealed that metastases formed more often in certain organs, suggesting that those organs provide more fertile ground for tumor growth.
"The best work in the pathology of cancer is now done by those who ... are studying the nature of the seed," he concluded. "They are like scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful."
How right he was.
The "soil" in which a tumor develops is a complex system of many cell types, diffusible growth factors, and the structural components of the extracellular matrix. Cells in the tumor microenvironment include vascular cells (endothelial cells, pericytes and smooth muscle cells), cells that respond to infection and injury (lymphocytes, macrophages and mast cells), and fibroblasts. Taken together, these components are called the "stroma," and it is the tumor-stroma interactions that ongoing research efforts seek to understand.
"There has been a growing appreciation that a tumor really is like an organ," Mohla says. "Tumors are not masses of autonomous cells; they are more like organs with their own vascular supplies, immune cells, structural matrix ... and both the tumor and the stroma are co-evolving.
"To understand the continuum of cancer biology from initiation all the way to metastasis, we must focus on the tumor microenvironment."
This long-recognized concept of a tumor as an organ – a concept pathologists have "always known," Matrisian says – was overlooked in the hubbub that accompanied discovery of the first oncogene in 1970.
"We got very involved, for 30 years, on what happens inside the cancer cell, on the genetic changes that occur and cause tumorigenesis," Matrisian says.
This focus wasn't all bad; it contributed enormously to our understanding of oncogenes, tumor suppressor genes and signaling pathways, and to the development of successful targeted anti-cancer therapies like Gleevec and Herceptin.
Microenvironment trumps genetics
While most of the cancer research community focused on defining genetic mutations in the fast-growing cancer cells, some investigators continued to probe the interactions of the tumor with its stroma.
The potential of a normal microenvironment to suppress
tumorigenic potential was first reported in the 1970s. In a series of publications, investigators at the University of Pennsylvania and at the Fox Chase Cancer Center in Philadelphia showed that mouse teratocarcinoma cells – highly malignant cells that form tumors composed of varied tissue types – could develop normal tissues and generate normal mice when they were injected into early stage mouse embryos.
The studies "provided a striking exposition of the power of tissue context to modify the malignant potential of cancer cells," wrote Mina Bissell, Ph.D., Distinguished Scientist at Lawrence Berkeley National Laboratory, in a 2003 review. But "the implications of these experiments, that genetic alterations could be trumped by the microenvironment, were not widely appreciated as the oncogene paradigm and the importance of genetic changes in cancer rapidly took hold."
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