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

Abstract

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.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…The identification of tumor perfusion as a key parameter for the efficacy of immunotherapy also highlights the potential use of perfusion measures as markers for immunotherapy prediction Table S1). (62). To date, there are no universal predictive biomarkers for ICBs.…”

What is normal? Apelin and VEGFA , drivers of tumor vessel abnormality

“…The underlying cause of the aberrant tumor vasculature is commonly the production of the hypoxia‐regulated vascular endothelial growth factor (VEGF), in particular VEGFA. Neutralizing antibodies targeting VEGFA or the ligand binding site on its receptor, VEGFR2, have been available in the clinic for more than a decade by now and have been tested in many different cancers with relatively limited clinical benefit overall (Martin et al , ). Small molecular weight tyrosine kinase inhibitors have been more successful perhaps since they as a rule act on several related receptor tyrosine kinases (for a review, see Yunus et al , ).…”

“…Are there differences between vessels in different tumor types, in different organs, with regard to the underlying molecular mechanisms leading to the abnormal morphology and function of tumor vessels? Many cell types in the tumor microenvironment including tumor cells themselves, cancer‐associated fibroblasts, perivascular cells, and immune cells may contribute to the abnormality, for example, by secretion of cytokines including but not limited to VEGFA (Martin et al , ). A key question is therefore how stable normalization can be achieved and whether cancer‐specific strategies for stable normalization must be employed.…”

Exosomes mediate intercellular transfer of non–autonomous tolerance to proteasome inhibitors in mixed‐lineage leukemia

“…Drug‐resistant cancer cells can not only emerge from the treatment‐mediated selection of subpopulations that present at the start of therapy but also from a general adaptation process under therapy stress. Moreover, the microenvironment and pharmacokinetic conditions of solid tumors as well as hematological malignancies put cancer cells in different situations during therapy stress . As chemotherapy drugs poison the cancer, neighboring cancer cells respond to the carnage, triggering apoptosis and releasing signals that encourage the survival of nearby sensitive cells.…”