Fukumura Lab Research
Angiogenesis and Microcirculation in Physiological and Pathophysiological Settings
The long-term goal of my research is to uncover the fundamental nature of vascular biology in both physiological and pathophysiological settings, and to utilize this knowledge for detection and treatment of diseases. Together with outstanding collaborators, I have been developing and utilizing state of the art imaging techniques and animal models which led to the discoveries summarize below.
Role of NO in tumor angiogenesis, lymphangiogenesis, microcirculation and radiation therapy
Nitric oxide (NO) is a highly reactive mediator with a variety of physiological and pathological functions. NO increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability and thus, may facilitate tumor growth. Furthermore, NO mediates angiogenesis and vessel maturation predominantly through endothelial NO synthase. We also found that NO mediates lymph-angiogenesis and metastasis as well as function of lymphatic vessels. We recently uncovered that restoration of perivascular NO gradients improves structure and function of both blood and lymphatic vessels, and response to radiation.
Role of tumor-host interactions in angiogenesis, tumor growth and metastasis
Using genetically engineered mouse and tumor models as well as in vivo imaging techniques, we found for the first time that nontransformed stromal cells –including activated fibroblasts, bone marrow derived cells – are a major inducer of tumor angiogenesis and mediate the formation of abnormal microenvironment. Furthermore, various anti-angiogenic or molecularly targeting treatments result in the activation of host stromal cells leading to treatment resistance. Our recent data indicate that stromal cells in the primary tumor travel with tumor cells and facilitate survival and growth of metastatic tumors. Controlling tumor-host interaction is an promising approach to facilitate tumor treatment. For example,, the blockade of vascular endothelial growth factor signaling can transiently normalize tumor vasculature and potentiate anti-tumor cytotoxic therapies.
Probing tumor microenvironment using nanotechnology
We have been studying the tumor microenvironment and transport properties using nano-probes. We found that relatively large nanoparticles – size of current nanomedicine – can take advantage of enhanced permeability and retention effect for transvascular transport but are unable to penetrate into tumor tissues. We also found superior transvascular transport of rod-shape over spherical nanoparticles. Furthermore, we discovered that neutral charge is the best for interstitial transport. These findings led us to develop multistage nanotherapeutics that shrink upon the entry to the tumor microenvironment in order to facilitate interstitial transport.
Role of obesity in angiogenesis, tumor growth and treatments.
First, we established in vivo system to investigate blood vessel formation during adipogenesis. Using genetic inhibition of PPAR? and pharmacological inhibition of VEGFR2 signaling we found provocative reciprocal regulation of adipogenesis and angiogenesis, suggesting a novel strategy to treat obesity related diseases including cancer. We then established a physiologically based mathematical model and found that leptin pathway plays a key role in maintenance of body mass and its disruption destroys the body weight balance. We are currently studying the underling mechanisms of obesity-induced aggravation of breast cancer through both preclinical studies and clinical trials of breast cancer patients.
Engineering blood vessels
A major limitation of tissue engineering is the lack of functional blood and lymph vessels. First, we established a model to monitor tissue engineered blood vessels in vivo using MPLSM. We found that mesenchymal precursor cells accelerate remodeling of 3-D endothelial cell structure to functional blood vessels, differentiate into peri-vascular cells, and stabilize engineered vessel network for up to a year. Using this tissue engineered blood vessel model,.we then, showed that human ES cell, cord blood and peripheral blood -derived endothelial cells form functional blood vessels in vivo and that human bone marrow derived mesenchymal stem cells serve as perivascular precursor cells, mature and stabilize blood vessels. Detail observation of vessel anastomosis in these tissue-engineered blood vessels revealed a novel mechanism – wrapping-and-tapping of host vessels. More recently, we have established robust protocols deriving endothelial cells and mesenchymal precursor cells from induced pluripotent stem (iPS) cells and successfully generated blood vessels these iPS-derived cells
Optimized exercise therapy induces vessel normalization, boosts antitumor effector cell infiltration and function, and delays tumor growth in a CXCR3 pathway/CD8+ T cell- dependent manner. This results in sensitization of refractory breast cancer to immune checkpoint blockade.
Rakesh Jain and Dai Fukumura were named Highly Cited Researchers by Clarivate Analytics / Web of Science. Their research ranks among the top 1% most cited work.
Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2
“Deciphering and targeting mechanisms involved in resistance to anti-angiogenic therapy is critical to realizing the full potential of this promising cancer therapy,” says Dai Fukumura, MD, PhD, deputy director of the Steele Labs, co-senior author of the paper. “Not only is this the first report investigating the role in anti-angiogenic cancer therapy of a subset of innate immune cells – Ly6Clowor non-classical monocytes – it is also the first to find an immunosuppressive function for these cells and to identify that as the key mechanism conferring resistance to anti-angiogenic therapy.”
Fukumura Lab Team
Former Team Members
It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1ß. PSCs further secrete IL-1ß, and inactivation of PSCs reduces IL-1ß expression and TAN recruitment. Furthermore, depletion of TANs, IL-1ß inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.