Nav: Home

MGH team identifies possible mechanism for resistance to antiangiogenesis therapy

October 12, 2016

Massachusetts General Hospital (MGH) investigators have identified a potential mechanism behind the resistance that inevitably develops to cancer treatment with a combination of chemotherapy and antiangiogenic drugs. In a paper published in Science Translational Medicine the researchers report that treating metastatic colorectal cancer with the antiangiogenesis drugs such as bevacizumab (Avastin) significantly increases several components of the extracellular matrix and increases stiffness within liver metastases in both patients and mouse models.

"Systemic chemotherapy is a cornerstone of therapy for metastatic colorectal cancer, and the introduction of antiangiogenic drugs like bevacizumab has extended patients' survival, although the tumors ultimately progress," says Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, one of the study's co-senior authors. "Understanding how tumors become resistant to treatment could help us develop novel strategies to overcome those mechanisms of resistance."

Antiangiogenesis drugs were originally thought to improve cancer treatment by cutting off a tumor's blood supply. However, a hypothesis developed by Rakesh Jain, PhD, director of the Steele Lab and co-senior author of the current study that when given in judicious doses the drugs acted by normalizing the abnormal vasculature within a tumor, thus improving the delivery of chemotherapy drugs and response to radiation treatment - has been supported by many studies.

Another factor that can impede drug delivery within tumors is a buildup of compressive forces that squeeze blood vessels shut. In addition to the pressure exerted by proliferating tumor cells, the extracellular matrix surrounding the tumor cells also contributes to these forces. Some recent studies have found that the hypoxia -- reduction in oxygen supply - induced by antiangiogenic therapy increases the expression in primary tumors of collagen, a major component of the extracellular matrix. The MGH team set out to investigate whether other matrix components -- specifically hyaluronic acid (HA) and sulfated glycosaminoglycans (sGAGs) - were affected by antiangiogenic therapy and, if they were, contributed to treatment resistance.

The research team first studied samples of liver metastases from patients with colorectal cancer and found the HA expression was increased within tumors, compared with unaffected liver tissue, and was even higher in metastases from patients who had received antiangiogenic therapy. In two mouse models of metastatic colorectal cancer, they found that antiangiogenic treatment increased compressive forces within liver metastases by stiffening tissues. Expression of both HA and sGAG was significantly higher after antiangiogenic treatment in the mouse models. In addition, antiangiogenic therapy appeared to cause an influx of suppressor immune cells that would reduce any immune response against the tumor.

Analysis of metastatic tissue from the mouse models revealed increased hypoxia and decrease density of microvessels after antiangiogenic therapy, followed by measurable increases in HA and sGAG. Inducing hypoxia in human liver stellate cells, the primary source of extracellular matrix, lead to a more than fourfold increase in the expression of HA. Adding an enzyme that targets HA to antiangiogenesis treatment in one of the mouse models caused a 74 percent reduction in HA levels and prolonged the animals' survival, compared with combination chemotherapy and antiangiogenesis alone.

"Although various mechanisms of resistance to antiangiogenesis therapy have been suggested, our study is the first to propose a role for the extracellular matrix and alterations in the mechanical properties of tumors," says Fukumura, who is an associate professor of Radiation Oncology at Harvard Medical School. "In addition to showing for the first time that antiangiogenesis therapy changes these properties within tumors, we also found that the hypoxia induced by extracellular matrix abnormalities attracts the immunosuppressive cells that help the tumor evade a systemic immune cell attack."

The authors note that their findings in animal models need to be validated in controlled clinical trials in human patients. "If these trials are successful, 'normalizing' the matrix may improve treatment outcomes in multiple cancers, since these tumors harbor an excessive quantity of abnormal extracellular matrix," Jain, who is also the Cook Professor of Radiation Oncology (Tumor Biology) at HMS.
-end-
In addition to Jain and Fukumura, additional coauthors include Nuh N. Rahbari, MD, the first author of the study, a research fellow in the Steele Lab. Support for this study includes National Institutes of Health grants CA080124, T32 DK007191, CA126642, CA197743, CA096915, CA139168, CA159258, CA098706 and CA173518.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School.

The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Chemotherapy Articles:

Chemotherapy drug may increase vulnerability to depression
A chemotherapy drug used to treat brain cancer may increase vulnerability to depression by stopping new brain cells from growing, according to a new King's College London study out today in Translational Psychiatry.
Sperm changes documented years after chemotherapy
A Washington State University researcher has documented epigenetic changes in the sperm of men who underwent chemotherapy in their teens.
Depressed patients are less responsive to chemotherapy
A brain-boosting protein plays an important role in how well people respond to chemotherapy, researchers report at the ESMO Asia 2016 Congress in Singapore.
Breast cancer study predicts better response to chemotherapy
It is known from previous research that the ER-beta estrogen receptor often has a protective effect.
Personalizing chemotherapy to treat pediatric leukemia
A team of UCLA bioengineers has demonstrated that its technology may go a long way toward overcoming the challenges of treatment for acute lymphoblastic leukemia, among the most common types of cancer in children, and has the potential to help doctors personalize drug doses.
How gut microbes help chemotherapy drugs
Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report Oct.
Molecule prevents effect of chemotherapy
For the last three years the research team has been working on the development of a so-called biomarker to predict treatment effectiveness.
Study provides new clues to leukemia resurgence after chemotherapy
For the first time, researchers have discovered that some leukemia cells harvest energy resources from normal cells during chemotherapy, helping the cancer cells not only to survive, but actually thrive, after treatment.
Dialing up chemotherapy for pancreatic cancer with ultrasound
Researchers at Haukeland University Hospital in Bergen, Norway have combined a laboratory ultrasound technique called 'sonoporation' with the commercially-available chemotherapy compound Gemcitabine to increase the porosity of pancreatic cells with microbubbles and to help get the drug into cancer cells where it is needed.
Vitamin A may help improve pancreatic cancer chemotherapy
The addition of high doses of a form of vitamin A could help make chemotherapy more successful in treating pancreatic cancer, according to an early study by Queen Mary University of London.

Related Chemotherapy Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...