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Review
. 2019 Feb 10:81:505-534.
doi: 10.1146/annurev-physiol-020518-114700.

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

John D Martin  1 , Giorgio Seano  2 , Rakesh K Jain  3
Affiliations
Review

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

John D Martin et al. Annu Rev Physiol. .

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.

Keywords: angiogenesis; hypoxia; immunostimulation; normalization; tumor microenvironment.

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Figures

Figure 1
Figure 1
Chronology of vascular normalization in preclinical and clinical studies. This time line shows the key concepts and findings related to vascular and cancer-associated fibroblast/extracellular matrix normalization from the senior author’s laboratory. References for the bottom panels can be found in Reference 4. Abbreviations: AAT, antiangiogenesis therapies; ASI, angiotensin system inhibitor; CRC, colorectal cancer; FDA, Food and Drug Administration; GBM, glioblastoma; HCC, hepatocellular carcinoma; ICB, immune checkpoint blocker; NSCLC, non-small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; TME, tumor microenvironment.
Figure 2
Figure 2
(a,b) Angiogenesis, desmoplasia, and inflammation promote a cycle characterized by leaky and compressed tumor vessels. (a) Intravital microscopy image of murine tumor vessels (black; negative contrast). At 24 h postinjection, 90-nm liposomes (red) are extravasated from and accumulated around leaky tumor vessels. The liposomes’ extravasation is heterogeneous. Panel adapted from Reference 156. (b) Histological image of murine tumor vessels. Most vessels are nonperfused (red) in this collagen-rich (blue) tumor, and there is a lack of blood flow (yellow). Panel adapted from Reference 52. (c,d) Schematics of perfusion before and after normalization. (c) In the top images, the schematics depict untreated tumor vessels, with one vessel having limited flow (few red blood cells), and the other vessel is well perfused (many red blood cells). The tissue around the perfused vessel is normoxic (pink), whereas the tissue farther from the vessels is hypoxic (purple). The region of normoxia surrounding each vessel is denoted by a black dashed line. Vessel fortification occurs when pericytes are recruited and basement membrane is repaired to produce an intact perivascular layer (green), which leads to increased blood flow that produces normoxia in the surrounding tissue. (d) Vessel decompression occurs after solid stress is alleviated. The decompressed blood vessel is reperfused, and normoxia around the vessel is restored. (e,f) Normalization results in homogeneous perfusion throughout tumors. (e) In untreated tumors (green, top), perfused vessels are heterogeneous and of limited density (orange). Fortifying, not pruning, vascular normalization produces a homogeneous distribution of perfused vessels (bottom). Panel adapted from Reference 19. (f) In untreated tumors (top), collagen (blue) and other components of desmoplasia promote vessel compression, such that large regions lack perfused vessels (green). Cancer-associated fibroblast/extracellular matrix (CAF/ECM) normalization (bottom) reduces collagen and reperfuses compressed vessels. Panel adapted from Reference 52.
Figure 3
Figure 3
Pathways that facilitate or hinder vascular normalization. Several pathways in multiple cell types can facilitate (green) or hinder (red) vessel normalization. The cancer cell is depicted near endothelial cells to save space. Figure adapted from Reference 2.
Figure 4
Figure 4
Pathways that facilitate or hinder cancer-associated fibroblast/extracellular matrix (CAF/ECM) normalization. Several pathways promote activated, protumor CAFs (pink), but these cells can be reprogrammed to a quiescent phenotype (green). Abbreviations: COL1, collagen 1; CTGF, connective tissue growth factor; HA, hyaluronic acid; HAS, hyaluronan synthase; PDGF, platelet-derived growth factor; Shh, Sonic hedgehog; TGF-β, transforming growth factor-β.
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