Penn State College of Medicine researchers, in collaboration with colleagues at the University of Southern California, have taken an important step in understanding the role of cancer. Using a unique approach that involves study of individual cells, the team, led by C. Bart Rountree, M.D., has demonstrated for the first time a population of cancer stem cells in the liver prior to tumor formation. The research, published in the journal Stem Cells, shows a potential link between liver stem cells and liver cancer.

Using a liver-specific PTEN (phosphatase and tensin homolog deleted on chromosome 10) mouse model allowed Rountree and his colleagues to study the microenvironment of the liver without affecting the rest of the mouse.

“The PTEN knock-out mouse is one model of chronic liver injury that ultimately leads to liver cancer. During chronic injury, liver stem cells proliferate, and at times of healthy liver, the liver stem cells are very rare,” Rountree said. “We were initially looking for what is driving liver stem cell proliferation during chronic liver injury.

“We started investigating liver stem cells in many different liver injury models with the idea we may be able to help people with liver disease, but we discovered that some cells we isolated were malignant,” Rountree said. “It was quite a surprise for us because there were not any tumors in the mice when we isolated the cells.”

The liver is the only organ in the body that is able to fully regenerate itself. The cells of the liver, including hepatocytes and cholangiocytes, can divide and repopulate themselves. With chronic liver injury, including by a virus or alcoholism, the hepatocytes lose the ability to make more of themselves. In that setting, liver stem cells proliferate and can make either of the cell types. However, patients with chronic injury also develop liver cancer, opening the possibility that the stem cells are involved in tumor formation.

“There’s been a groundswell of interest in understanding the role of specific stem cells in the development of liver cancer,” Rountree said. “There is a cancer stem cell lurking out there that may be very bad. It has stem cell properties and is malignant, resistant to chemotherapy. These properties make it harder to treat these cancers.

“What we ended up doing was shifting our understanding of liver stem cells and their role in malignancy,” Rountree said. “All work previously done was looking at patients, animal models or cell lines after the tumor already developed. What we did was identify malignant stem cells before there is evidence of the primary tumor. This gave us a new perspective on not only what the potential of stem cells for therapy is, but also in terms of what’s driving cancer formation. Imagine treating a cancer before a primary malignancy forms.”

Researchers created ten cell lines to study using a single-cell isolation technique. Cells that make a unique surface protein called CD133 were separated by placing them in a liquid medium and running through a flow cytometer. Once identified, a robot took a single CD133-positive cell and placed it in a single drop into one well of a culture dish. Doing this several hundred times, the cell lines were established.

These single cells, when expanded up, had stem cell characteristics, having markers of both hepatocytes and cholangiocytes. When these lines were injected into a mouse with a deficient immune system, the tumors then formed.

Rountree said there is interest in targeting these stem cells with malignant potential. “Can we target these cells in patients with hepatitis B or C, either before or after their cancer forms?” Rountree said. “The broader implication is very powerful. If you look at a patient with chronic injury and find a way to specifically target cells with malignant potential, you may be able to prevent liver cancer in the first place.”

Other researchers involved in the study are Wei Ding, M.D., Ph.D., Penn State College of Medicine; and Lina He and Bangyan Stiles, Ph.D., of University of Southern California, Los Angeles. This study was funded by the National Institute of Health and the American Gastroenterological Association.

Source:
Matthew G. Solovey

Penn State Hershey Medical Center, Penn State College of Medicine

The University of Southern California has been selected to establish a $16 million cancer research center as part of a new strategy against the disease by the U.S. National Institutes of Health and its National Cancer Institute.

The five-year award will create a National Cancer Institute Physical Science-Oncology Center based at USC and involving a consortium of universities. Partnering in the USC grant will be Arizona State University, the California Institute of Technology, Cold Spring Harbor Laboratory, New York University, Stanford University, the University of Arizona and the University of Texas at Austin.

The Physical Science-Oncology Center initiative differs from past cancer research programs. While cancer biologists often work with scientists in other fields, this marks the first large-scale recruitment of outside scientists in the battle against the disease.

Noted technology innovator and entrepreneur W. Daniel Hillis, research professor of engineering at the USC Viterbi School of Engineering and professor of research medicine at the Keck School of Medicine of USC, is the principal investigator for the effort.

“This funding allows us to bring together a unique team of physicists, mathematicians, engineers and biologists to work together with physicians on the understanding and treatment of cancer,” said Hillis, who is also co-chairman of Applied Minds Inc. and a former Disney Imagineering executive.

The new center is one of 12 in the nation to receive the designation as a Physical Science-Oncology Center.

“By bringing a fresh set of eyes to the study of cancer, these new centers have great potential to advance, and sometimes challenge, accepted theories about cancer and its supportive microenvironment,” said John E. Niederhuber, director of the National Cancer Institute. “Physical scientists think in terms of time, space, pressure, heat and evolution in ways that we hope will lead to new understandings of the multitude of forces that govern cancer - and with that understanding, we hope to develop new and innovative methods of arresting tumor growth and metastasis.”

The five-year grant will allow the USC center to focus on creating a set of “virtual cancer” models based on measurements from individual cancer patients. The models then would be used to simulate cancer growth and predict drug responses for each patient.

“Clinical tools to accurately describe, evaluate and predict an individual’s response to cancer therapy are a field-wide priority,” said David Agus, senior co-investigator on the grant and professor of medicine at the Keck School of Medicine and director of the USC Center for Applied Molecular Medicine and the USC Westside Prostate Cancer Center. “The center brings to USC a network of scientists from multiple disciplines to try and control cancer with new ideas.”

The USC-led consortium will develop a single, integrated, virtual cancer model that describes cancer’s complexity from the smallest interactions at the molecular-cellular level to large-scale phenomena of how a tumor interacts with its host.

Specifically, the consortium will model: networks of interactions at the molecular and cellular levels; tumor molecular phylogenetic evolution; tumor growth, invasiveness and vasculature; and tumor interaction with host factors and the immune system.

“The models we are going to develop are based on a dataset spanning the many facets of cancer as interrogated by a suite of novel measurement platforms. Our unique dataset will enable us to rigorously describe cancer as the complex system it is,” said Parag Mallick, assistant professor of research at the Keck School of Medicine, one of the project co-leaders who played a critical role in writing the grant establishing the center at USC. “We will be primarily describing therapeutic response of non-Hodgkins lymphoma to standard chemotherapy, but additionally ensuring the generality of our approach by investigating acute myelogenous leukemia and non-small-cell lung cancer.”

According to USC Executive Vice President and Provost C. L. Max Nikias, “This grant honors outstanding interdisciplinary research efforts that have transformational potential within the biological and medical sciences. USC is honored to lead a consortium of such a high caliber.”

The winning grant proposal was assembled and submitted with the guidance of USC’s Washington, D.C. Research Advancement Office. “We greatly appreciate the effort of Steven Moldin, executive director of research advancement, and his colleagues who brought together all the various universities and institutes into the research project,” said Randolph Hall, USC vice provost for research advancement. “Without their efforts, the grant would not have been submitted.”

In addition to the research partner institutions, the USC-led initiative features consulting researchers from several academic, industry and institutional partners, including: Prognosys BioSciences, the Translational Genomics Research Institute, Princeton University, the University of California, Irvine, the Santa Fe Institute, Applied Proteomics and Applied Minds.

Noteworthy consultants and collaborators include Stanford’s Sanjiv Gambhir, Cold Spring Harbor Laboratory’s Scott Lowe and the Santa Fe Institute’s Nobel Laureate Murray Gell-Mann.

About the NIH/NCI Physical Science-Oncology Center Initiative

The National Cancer Institute is launching a network of 12 centers that will bring a new cadre of theoretical physicists, mathematicians, chemists and engineers to the study of cancer. During the five-year initiative, the Physical Sciences-Oncology Centers will take new, non-traditional approaches to cancer research by studying the physical laws and principles of cancer; evolution and evolutionary theory of cancer; information coding, decoding, transfer and translation in cancer; and ways to de-convolute cancer’s complexity.

The National Cancer Institute has awarded grants to 12 Physical Science-Oncology Centers which will be the focal points of a research network that will span the country. The 12 institutions are:

- Arizona State University

- Cornell University
- H. Lee Moffitt Cancer Center & Research Institute

- Johns Hopkins University
- Massachusetts Institute of Technology

- Memorial Sloan-Kettering Cancer Center

- Northwestern University
- Princeton University
- Scripps Research Institute

- University of California, Berkeley

- University of Southern California

- University of Texas Health Science Center (Houston)

Each of the Physical Science-Oncology Centers has convened groups of experts that individually and collectively will support and nurture a transdisciplinary environment and promote research that originates and tests novel, non-traditional, physical sciences-based approaches to understand and control cancer; generates independent sets of physical measurements and integrates them with existing knowledge of cancer; and develops and evaluates approaches from the physical sciences to provide a comprehensive and dynamic picture of cancer.

Ultimately, through coordinated development and testing of novel approaches to studying cancer processes, the network of Physical Science-Oncology Centers is expected to generate new bodies of knowledge in order to identify and define critical aspects of physics, chemistry and engineering that operate at all levels in cancer processes.

More information about the Physical Science-Oncology Centers program can be found at http://physics.cancer.gov

For more information on the USC Physical Science-Oncology Center, visit here.

Source
University of Southern California