Scientists have known for some time that biological molecules interact with one another in a similarly complex pattern. Now researchers at the Stanford University School of Medicine have determined that hamstringing these molecular powerbrokers is a good way to derail processes such as cancer development.
"It's like social networking," said Paul Khavari, MD, PhD, professor of dermatology at the medical school. "If you take the most highly interconnected person and somehow hinder his access to a computer, the network may fall apart." Although the Stanford researchers were focusing on tumor invasion and metastasis, their expectation is that a similar approach could be used to identify potential targets for many different diseases.
Khavari, who is also a member of Stanford's Cancer Center and Bio-X, is the senior author of the research, which will be published in the June issue of Cancer Cell. He is also the clinical chief of the dermatology service at the Veterans Affairs Palo Alto Health Care System.
Khavari and genetics graduate student Jason Reuter used the concept of biological networks to investigate how cancers progress from a growing lump of unruly cells to an invasive, potentially deadly tumor. They found that inhibiting a molecule called beta-1 integrin blocked the ability of the cells to grow and invade surrounding tissue.
"Ninety percent of all human tumors, including breast, lung, prostate, colon, pancreatic and skin cancers, arise in the epithelial tissue that lines body surfaces," said Khavari. "None of these tumors become highly dangerous to a person unless they invade through the underlying basement membrane and begin to spread to other tissue."
To conduct the research, Khavari and Reuter devised the first-ever three-dimensional model of inducible human tissue tumor development by grafting genetically engineered human skin tissue onto mice with compromised immune systems. They then treated the mice with a compound that activated an introduced cancer-causing gene in the modified human tissue, and monitored gene expression in the tumor and the surrounding tissue as the skin cancer developed and began to invade.
"This approach has been able to recapitulate in real time the progression from normal epithelial tissue to invasive cancer," said Khavari, "and now this model is being used to systematically identify the key genes in this process." He and Reuter identified more than 700 genes whose expression patterns deviated from normal during cancer development. They used an existing database to map the genes into functional networks, which varied as the tumor developed.
"A specific set of genes emerged during early tumor development," said Khavari, "which gave way to others as the tumor began to invade surrounding tissue." During early growth, for example, the researchers identified networks in the cancer cells that were involved in cell division and in the surrounding tissue that were involved in the formation of blood vessels to feed the growing tumor. As the cancer progressed, they saw the emergence of networks involved in cell movement and attachment and in remodeling of the extracellular matrix.
As in the Facebook example, the researches focused on those gene products in the networks that were the most highly connected. Sixteen of the top 25 molecules are found either on the surface or between the tumor cells, indicating that the tumor is actively involved in remodeling its surrounding environment. Beta-1 integrin, a member of a family of proteins involved in mediating attachments between cells, was the third-most well-connected. Khavari and Reuter found that blocking the activity of beta-1, which has been implicated in the growth of several human cancer cell lines, slowed the growth of both established and newly developing tumors in their model and seemed to lead to a more clearly defined border between the tumor cells and the surrounding normal tissue.
"Beta-1 integrin proved important in the co-evolution of the tumor and its supporting framework, the stroma, toward malignancy," said Khavari. He and his lab members plan to continue their analysis of other genes in the network, and to try to optimize their model for other types of cells and cancers. "We are working to build models like this for many other epithelial tissues so we can begin to identify the underlying global mediators of cancer progression."
In addition to Khavari and Reuter, other Stanford researchers involved in the study include postdoctoral scholars Susana Ortiz-Urda, MD, PhD; Anna Pasmooij, PhD; and Markus Kretz, PhD; graduate student John Garcia; research associate Florence Scholl, PhD; and associate professor of dermatology Howard Chang, MD, PhD. The research was funded by the Veterans Affairs Office of Research and Development and by the National Institutes of Health.
The Stanford University School of Medicine consistently ranks among the nation's top 10 medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
Krista Conger | EurekAlert!
Further reports about: > Beta-1 > Cancer > Dermatology > Health > Health Care System > Medicine > biological molecules > blood vessel > cancer development > cancer-causing gene > epithelial tissue > extracellular matrix > functional networks > human tissue > immune system > skin cancer > tumor cells > tumor development
Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie
Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...
Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.
A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
21.04.2017 | Physics and Astronomy
21.04.2017 | Health and Medicine
21.04.2017 | Physics and Astronomy