Why do some cancers spread while others don’t? Scientists have now demonstrated that metastatic incompetent cancers actually “poison the soil” by generating a microenvironment that blocks cancer cells from settling and growing in distant organs. The “seed and the soil” hypothesis proposed by Stephen Paget in 1889 is now widely accepted to explain how cancer cells (seeds) are able to generate fertile soil (the microenvironment) in distant organs that promotes cancer’s spread. However, this concept had not explained why some tumors do not spread or metastasize.
The researchers, from Weill Cornell Medical College, found that two key proteins involved in this process work by dramatically suppressing cancer’s spread. The study offers hope that a drug based on these potentially therapeutic proteins, prosaposin and Thrombospondin 1 (Tsp-1), might help keep human cancer at bay and from metastasizing.
Scientists don’t understand why some tumors wouldn’t “want” to spread. It goes against their “job description,” says the study’s senior investigator, Vivek Mittal, Ph.D., an associate professor of cell and developmental biology in cardiothoracic surgery and director of the Neuberger Berman Foundation Lung Cancer Laboratory at Weill Cornell Medical College. He theorizes that metastasis occurs when the barriers that the body throws up to protect itself against cancer fail. But there are some tumors in which some of the barriers may still be intact. “So that suggests those primary tumors will continue to grow, but that an innate protective barrier still exists that prevents them from spreading and invading other organs,” says Dr. Mittal.
The researchers found that, like typical tumors, metastasis-incompetent tumors also send out signaling molecules that establish what is known as the “premetastatic niche” in distant organs. These niches composed of bone marrow cells and various growth factors have been described previously by others including Dr. Mittal as the fertile “soil” that the disseminated cancer cell “seeds” grow in.
Weill Cornell’s Raúl Catena, Ph.D., a postdoctoral fellow in Dr. Mittal’s laboratory, found an important difference between the tumor types. Metastatic-incompetent tumors systemically increased expression of Tsp-1, a molecule known to fight cancer growth. Importantly, increased Tsp-1 production was found specifically in the bone marrow myeloid cells that comprise the metastatic niche. These results were striking, because for the first time the bone marrow-derived myeloid cells were implicated as the main producers of Tsp-1, says Dr. Mittal.
In addition, Weill Cornell and Harvard researchers found that prosaposin secreted predominantly by the metastatic-incompetent tumors increased expression of Tsp-1 in the premetastatic lungs. Thus, prosaposin works in combination with Tsp-1 to convert pro-metastatic bone marrow myeloid cells in the niche into cells that are not hospitable to cancer cells that spread from a primary tumor. “The very same myeloid cells in the niche that we know can promote metastasis can also be induced under the command of the metastatic incompetent primary tumor to inhibit metastasis,” Dr. Mittal says.
The research team found that the Tsp-1–inducing activity of prosaposin was contained in only a 5-amino acid peptide region of the protein. This peptide alone induced Tsp-1 in the bone marrow cells and effectively suppressed metastatic spread in the lungs in mouse models of breast and prostate cancer. This 5-amino acid peptide with Tsp-1–inducing activity has the potential to be directly used as a simple and safe therapeutic agent against metastatic cancer, says Dr. Mittal. The scientists have begun to test prosaposin in other tumor types or metastatic sites.
“The study’s findings have clinical implications,” Dr. Mittal says. “Not only is it theoretically possible to design a prosaposin-based drug or drugs that induce Tsp-1 to block cancer spread, but you could potentially create noninvasive prognostic tests to predict whether a cancer will metastasize.”
The study was reported in the April 30 issue of Cancer Discovery, in a paper titled “Bone Marrow-Derived Gr1+ Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1”.