The study is being published the week of June 18, 2007 in an advanced online edition of the Proceedings of the National Academy of Sciences.
Until this study, the significance of pleiotrophin (PTN) expression in breast cancer had not been clearly established. These new findings could lead to a better understanding of the molecular pathogenesis of breast cancer and focus attention on PTN and its signaling pathway as possible targets for new cancer therapies.
The study also found that the expression of pleiotrophin activated surrounding cells to remodel the tumor microenvironment, induced tumor angiogenesis, and increased the number of receptors for different markers of aggressive breast cancers.
“Breast cancers progress through stages of increasing malignancy triggered by mutations that promote their growth,” said Thomas Deuel, the Scripps Research scientist whose laboratory made the discovery. “The major finding of our study demonstrates both in vivo and in vitro that inappropriate expression of PTN not only promotes breast cancer progression but that by itself PTN secretion from human breast cancer cells may be sufficient to shift that progression to a more aggressive form of breast cancer.”
In the study, three models were tested to determine if inappropriate expression of PTN alone was sufficient to induce breast cancer or whether the cytokine cooperates with different pathogenic mechanisms to stimulate breast cancer progression.
The new study identified PTN as one factor that activates stromal cells-cells found in the loose connective tissue-and induces several features of aggressive breast cancer. While the importance of these cancer cell-stromal cell interactions is well established, only limited progress has been made in identifying the factors that cause stromal cells to initiate tumor progression.
“Our breakthrough findings demonstrate that PTN-activated stromal cells are responsible for the ultimate remodeling of extracellular matrix proteins, as well as the release of factors that stimulate the growth of malignant cancer cells,” Deuel said. “We’ve shown that PTN secreted from breast cancer cells is the key mechanism of stromal cell activation, and that PTN alone is sufficient to stimulate many of the critical signaling pathways that aggressively promote breast cancer progression.”
Using genetically modified mouse models, the study found that the inappropriate expression of PTN produced breast cancers of a more aggressive subtype. In those same mouse models, highly malignant cells of scirrhous carcinoma-a hard, fibrous tumor-were found to express very high levels of the mouse mammary tumor virus (MMTV)-Ptn transgene along with increases in collagen, elastin, tumor angiogenesis, and increased size of new blood vessels within the breast cancers-all markers for breast cancer.
“Our study suggests the possibility that PTN expression may account for many of the features of scirrhous carcinoma seen in the breast cancers of these mice,” Deuel said. “Pleiotrophin stimulates new collagen of different subtypes and new elastin synthesis. Collagen fragments are known to stimulate growth of carcinoma cells and to stimulate anti-apoptotic pathways, favoring growth of the carcinoma cells.”
Other authors of the study, Secretion of Pleiotrophin Stimulates Breast Cancer Progression Through Remodeling of the Tumor Microenvironment, include Yunchao Chang, Masahiko Zuka, and Pablo Perez-Pinera of The Scripps Research Institute; Aurora Astudillo of the Hospital Universitario Central de Asturias, Oviedo, Spain; Joanne Mortimer of the University of California San Diego; and James R. Berenson of the Institute for Myeloma and Bone Cancer Research, Los Angeles.
The study was supported by the National Institutes of Health and The Skaggs Institute for Chemical Biology.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
Journal
Proceedings of the National Academy of Sciences