Cell biology

Immunosuppression

Biology

Extracellular matrix

Hypoxia (environmental)

Pancreatic cancer

Organic chemistry

Bioinformatics

Oxygen

Desmoplasia

Tumor microenvironment

Internal medicine

Cancer therapy

Medicine

Chemistry

Lymphatic system

Cancer

Pathology

Annual Review of Physiology

Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents—originally developed to starve tumors—could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges