AACR, Author Interviews, Breast Cancer, Cancer Research, Pancreatic, Weight Research / 13.02.2016
Breast and Pancreatic Cancer: Pathway Identified That Accelerates Tumors in Obese Patients
MedicalResearch.com Interview with:
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Dr. Joao Incio[/caption]
Joao Incio, MD
Edwin L. Steele Laboratory for Tumor Biology
Massachusetts General Hospital | Harvard Medical School | Boston, MA, U.S.A
Department of Internal Medicine | Hospital S. Joao | Porto, Portugal
Medical Research: What is the background for this study? What are the main findings?
Dr. Incio: The study focused on the effects of obesity on pancreatic and breast cancer, since more than half of those diagnosed with such tumors are overweight or obese. In addition, a number of large-scale studies have found that obesity leads to an increased risk of death in pancreatic, breast and other types of cancer. But prior to the current study the mechanism of obesity-induced pancreatic and breast cancer progression was unclear. We have uncovered a novel mechanism behind the ability of obesity to promote cancer progression. We found an association between obesity and an overabundance of a factor called PlGF (placental growth factor) and that PlGF’s binding to its receptor VEGFR-1, which is expressed on immune cells within tumors, promotes tumor progression.
We found that obesity increased infiltration of tumor-promoting immune cells and the growth and metastasis of pancreatic cancers. Blocking VEGFR-1 signaling shifted the immune environment towards prevention of tumor progression in obese but not in lean mice in both pancreatic and breast cancer models. We also found that PlGF was present in excess in obesity and that reduction of PlGF produced similar results to VEGFR-1 inhibition in the tumors of obese mice. We also discovered that targeting the PlGF/VEGFR-1 interaction prevents weight gain in a genetically obese mouse model but worsens a diabetes-like condition, a worsening that was alleviated by use of the common diabetes drug metformin, which also had beneficial anti-tumor effects.
Our findings in cellular and animal models, as well as in patient tumor samples, indicate that targeting the PlGF/ VEGFR-1 pathway may be particularly effective in obese patients.
Dr. Joao Incio[/caption]
Joao Incio, MD
Edwin L. Steele Laboratory for Tumor Biology
Massachusetts General Hospital | Harvard Medical School | Boston, MA, U.S.A
Department of Internal Medicine | Hospital S. Joao | Porto, Portugal
Medical Research: What is the background for this study? What are the main findings?
Dr. Incio: The study focused on the effects of obesity on pancreatic and breast cancer, since more than half of those diagnosed with such tumors are overweight or obese. In addition, a number of large-scale studies have found that obesity leads to an increased risk of death in pancreatic, breast and other types of cancer. But prior to the current study the mechanism of obesity-induced pancreatic and breast cancer progression was unclear. We have uncovered a novel mechanism behind the ability of obesity to promote cancer progression. We found an association between obesity and an overabundance of a factor called PlGF (placental growth factor) and that PlGF’s binding to its receptor VEGFR-1, which is expressed on immune cells within tumors, promotes tumor progression.
We found that obesity increased infiltration of tumor-promoting immune cells and the growth and metastasis of pancreatic cancers. Blocking VEGFR-1 signaling shifted the immune environment towards prevention of tumor progression in obese but not in lean mice in both pancreatic and breast cancer models. We also found that PlGF was present in excess in obesity and that reduction of PlGF produced similar results to VEGFR-1 inhibition in the tumors of obese mice. We also discovered that targeting the PlGF/VEGFR-1 interaction prevents weight gain in a genetically obese mouse model but worsens a diabetes-like condition, a worsening that was alleviated by use of the common diabetes drug metformin, which also had beneficial anti-tumor effects.
Our findings in cellular and animal models, as well as in patient tumor samples, indicate that targeting the PlGF/ VEGFR-1 pathway may be particularly effective in obese patients.
Dr. Dai Fukumura[/caption]
MedicalResearch.com Interview with:
Dai Fukumura, M.D., Ph.D.
Joao Incio, M.D.
and Rakesh K. Jain, Ph.D
Edwin L. Steele Laboratory
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Fukumura: This study focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, which accounts for almost 40,000 cancer death in the U.S. ever year. Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 percent have type 2 diabetes or are insulin resistant. Diabetic patients taking metformin – a commonly used generic medication for type 2 diabetes – are known to have a reduced risk of developing pancreatic cancer; and among patients who develop the tumor, those taking the drug may have a reduced risk of death. But prior to the current study the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.
We have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer. Metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer. We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix and by reprogramming immune cells to reduce inflammation. Our findings in cellular and animal models and in patient tumor samples also indicate that this beneficial effect may be most prevalent in overweight and obese patients, who appear to have tumors with increased fibrosis.
Dr. Orian-Rousseau[/caption]
MedicalResearch.com Interview with:
Prof. Dr. Véronique Orian-Rousseau
Group Leader
Karlsruher Institut für Technologie (KIT)
Institut für Toxikologie und Genetik (ITG)
Campus Nord
Karlsruhe Germany
Medical Research: What is the background for this study? What are the main findings?
Response: Our group is working on the role of cell adhesion molecules in development and in tumor progression and metastasis. One protein in focus is CD44, a molecule that controls proliferation, differentiation and survival of cells. We have shown that one member of this family, namely CD44v6 acts as a co-receptor for receptor tyrosine kinases (RTKs) such as MET and VEGFR-2. CD44v6 has a dual function. It controls both the activation and signaling from the RTKs. We have identified a sequence in CD44v6 that is crucial for its function as a co-receptor. From this sequence we made a peptide that inhibits MET and VEGFR2 activation and signaling.
The CD44v6 peptide was used in several independent mouse models of pancreatic cancer including the transgenic PDAC mouse model. It could inhibit the growth of the primary tumor, metastasis and in addition could eliminate already established metastases.
In addition, we could show that MET and CD44v6 expression correlates with poor prognosis and metastasis in a cohort of pancreatic cancer patients.
Dr. Jason Gold[/caption]
MedicalResearch.com Interview with:
Jason S. Gold MD FACS
Chief of Surgical Oncology, VA Boston Healthcare System
Assistant Professor of Surgery, Harvard Medical School
Brigham and Women’s Hospital
Medical Research: What is the background for this study?
Dr. Gold: Pancreas cancer is a lethal disease. While advances in the best available care for pancreas cancer are desperately needed, improvements can be made in addressing disparities in care. This study aimed to evaluate associations of social and demographic variables with the utilization of surgical resection as well as with survival after surgical resection for early-stage pancreas cancer.
Medical Research: What are the main findings?
Dr. Gold: The main findings are the following:
1: We found that less than half of patients with early-stage pancreas cancer undergo resection in the United States. Interestingly, the rate of resection has not changed with time during the eight-year study period.
2. We also found significant disparities associated with the utilization of surgical resection for early-stage pancreas cancer in the United States. African American patients, Hispanic patients, single patients, and uninsured patients were significantly less likely to have their tumors removed. There were regional variations in the utilization of surgical resection as well. Patients in the Southeast were significantly less likely to have a pancreas resection for cancer compared to patients in the Northeast.
3. Among the patients who underwent surgical resection for early-stage pancreas cancer, we did not see significant independent associations with survival for most of the social and demographic variables analyzed. Surprisingly, however, patients from the Southeast had worse long-term survival after pancreas cancer resection compared to those in other regions of the United States even after adjusting for other variables.
