Earlier this week Dr. Ari Melnick answered another question from Targeted Oncology concerning the challenges associated with measuring tumor heterogeneity in finding new avenues for targeted therapy.
Category: Laboratory Research
Tumor Blood Vessel Signals Linked to Cancer Lethality
Although the importance of blood vessels to cancer growth is well established, researchers at Weill Cornell Medical College recently found, that the cells that line the blood vessels of tumors are important in promoting the change of a slow-growing malignancy into aggressive, disease resistant strains.
Their finding, in the March 17 issue of Cancer Cell , challenges what was believed to be a fundamental dogma in cancer. It suggests that it is not simply the number of genetic mutations that occur in cancer cells that determines the aggressiveness of the disease. Rather, lethality occurs when the cancer hijacks the reparative function of blood vessels, a critical step that ensures tumor cells’ ability to spread and resist treatment.
The researchers also found the crucial nurturing molecules that cancer co-opts from tumor blood vessels to promote invasiveness and resistance to chemotherapy. They show in animal experiments that shutting down these previously unrecognized biological signals originating from tumor vessels makes cancer less aggressive and improves survival.
“The endothelial cells that line the vessels orchestrate a wide variety of biological processes — good and bad,” says the study’s senior investigator, Dr. Shahin Rafii, co-director of Weill Cornell’s Ansary Stem Cell Institute and Tri-Institutional Stem Cell Initiative, and a professor of Genetic Medicine. Dr. Rafii also is the founder of Angiocrine Bioscience, a startup anchored at Weill Cornell that is investigating how endothelial cells might be used to heal damaged tissues and regenerate organs – as well as target tumors. “The understanding and control of blood vessel function and how this changes the malignant behaviors of cancer cells is a transformative concept and will pave the way for designing innovative treatments that disrupt signals from the local environment housing the tumor cells- a strategy that has been unappreciated.”
Novel Therapeutic Strategies for Targeting the Lymphoma Microenvironment
Although conventional chemotherapy is primarily aimed at tumor cells, we now know of the importance of neighborhood cells, included within the tumor mass. These include endothelial cells and pericytes that form blood vessels, macrophages that mediate inflammation, and fibroblasts and extracellular matrix proteins that build matrix and scar tissues. The interaction between the tumor cells and their neighborhood is collectively known as the tumor microenvironment. Given the importance of the tumor microenvironment in maintaining tumor growth and developing resistance to conventional chemotherapy, novel strategies that target the microenvironment are under active investigation. Clinical researchers led by, Dr. Jia Ruan, have recently published 2 important studies on developing novel therapeutic strategies that target lymphoma angiogenesis (blood vessel formation) and lymphangiogenesis (lymphatic vessel formation) within the tumor microenvironment.
The first study was published in the leading hematology journal Blood in collaboration with Dr. Leandro Cerchietti, a lymphoma biologist, and Dr. Katherine Hajjar, a vascular biology expert, both at Weill Cornell Medical College. The study found that pericytes, the vascular accessory cells surrounding the endothelial cells, are important players in lymphoma tumor angiogenesis, and represent potentially novel therapeutic targets for anti-lymphoma therapy. Specifically, the Weill Cornell lymphoma researchers treated human diffuse large B-cell lymphoma (DLBCL) growing in mouse models with an oral drug called imatinib. This incapacitated a critical cell surface receptor within the pericytes, namely platelet-derived growth factor receptor β (PDGFRβ), which is important for the survival of the pericytes and its communication with the endothelial cells. As a result, lymphoma-associated microvascular blood vessel formation was reduced due to programmed-cell death of both pericytes and endothelial cells. This ultimately translated into therapeutic effect of lymphoma growth impairment. This study provided proof of principal that targeting non-tumor vascular cells within the lymphoma microenvironment can result in significant inhibition of lymphoma growth, providing the basis for more refined consideration of anti-angiogenesis as a treatment strategy for lymphoma patients.
The second study published in Cancer Research, in collaboration with Dr. Lijun Xia, a glycoprotein and vascular biology expert at the Oklahoma Research Foundation. The researchers found that 1) lymphatic vessels, which form the vascular network known as lymphangiogenesis, contributed to the growth and spreading of lymphomas in an experimental model of mantle cell lymphoma (MCL), and 2) treatment with the immunomodulatory drug lenalidomide potently inhibited the growth and spreading of MCL by disabling tumor lymphangiogenesis. Mechanistically the researchers demonstrated that treatment with lenalidomide reduced the number of MCL-associated macrophages and their production of a growth factor important for the formation of lymphatic vessels, namely vascular endothelial growth factor-C (VEGF-C). This is the first study to address the potential importance of lymphangiogenesis in lymphoma growth, and provided a novel perspective of the mechanisms of action of lenalidomide in lymphoma therapy. This pre-clinical study synergizes with our recent clinical data displaying high response rates and durable remissions with the biologic combination of lenalidomide + rituximab in patients with previously untreated MCL.
Both studies open potentially new novel paths to treating lymphoma, exemplifying the Lymphoma Program’s commitment to the bench-to-bedside translational research that brings cutting-edge science to patient care.
References
1. Blood. 2013 Jun 27:121(26):5192-202. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.
2. Cancer Res. 2013 Dec 15:73(24):7254-64. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma.
New Developments in Lymphoma 