Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models.
Intravital imaging techniques have provided unprecedented insight into tumor microcirculation and microenvironment. For example, these techniques allowed quantitative evaluations of tumor blood vasculature to uncover its abnormal organization, structure and function (e.g., hyper-permeability, heterogeneous and compromised blood flow). Similarly, imaging of functional lymphatics has documented their absence inside tumors. These abnormalities result in elevated interstitial fluid pressure and hinder the delivery of therapeutic agents to tumors. In addition, they induce a hostile microenvironment characterized by hypoxia and acidosis, as documented by intravital imaging. The abnormal microenvironment further lowers the effectiveness of anti-tumor treatments such as radiation therapy and chemotherapy. In addition to these mechanistic insights, intravital imaging may also offer new opportunities to improve therapy. For example, tumor angiogenesis results in immature, dysfunctional vessels--primarily caused by an imbalance in production of pro- and anti-angiogenic factors by the tumors. Restoring the balance of pro- and anti-angiogenic signaling in tumors can "normalize" tumor vasculature and thus, improve its function, as demonstrated by intravital imaging studies in preclinical models and in cancer patients. Administration of cytotoxic therapy during periods of vascular normalization has the potential to enhance treatment efficacy.
Fukumura
Dai
D
Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. dai@steele.mgh.harvard.edu
Duda
Dan G
DG
Munn
Lance L
LL
Jain
Rakesh K
RK
D000818:Animals; D001783:Blood Flow Velocity; D006801:Humans; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000473:pathology; D051379:Mice; D008833:Microcirculation; D008853:Microscopy / Q000379:methods*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D036641:Microscopy, Fluorescence, Multiphoton; D015335:Molecular Probes; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous
D015335:Molecular Probes