Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Jun 10;31(17):2205-18.
doi: 10.1200/JCO.2012.46.3653. Epub 2013 May 13.

Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers

Rakesh K Jain  1
Affiliations
Review

Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers

Rakesh K Jain. J Clin Oncol. .

Abstract

For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.

PubMed Disclaimer

Conflict of interest statement

Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
(A) The microenvironment is composed of blood and lymphatic vessels and a variety of nonmalignant host cells, all embedded in an extracellular matrix. The host cells include fibroblasts and a variety of resident and trafficking immune cells. (B) Vasculature of a brain tumor (upper left quadrant) and the surrounding brain of a mouse. Color overlay denotes scale of the depth of the vessel, with yellow vessels closest to the viewer, and red vessels deepest. Reproduced from.
Fig 2.
Fig 2.
(A) Transparent windows were implanted in the mammary gland, cranium, and dorsal skin of mice. Vasculature of breast tumors grown in these different sites is abnormal yet significantly different. Reproduced from. (B) The vasculature of the normal colon and that of a spontaneously arising colon cancer in a genetically engineered mouse model. Note that the blood vessels in a normal colon are highly organized. However, similar to transplanted tumors, the vessels in the spontaneous colon cancer are abnormal, and this abnormality increases as the tumor progresses over weeks 11 to 16. Reproduced from. (C) A polymer cast of the vasculature of a 1-lb human colon cancer. Note that this vasculature is as abnormal as that in the murine tumors. Reproduced from.
Fig 3.
Fig 3.
(A) Normalization hypothesis. Originally published by Scientific American, Inc. Illustration © 2013 Kasnot Illustration, Inc. All rights reserved.– (B) Blood perfusion in recurrent glioblastomas during treatment with cediranib, a pan–vascular endothelial growth factor receptor tyrosine kinase inhibitor. Note that the perfusion goes up in some patients, remains stable in others, and goes down in the rest. Data adapted. (C) Kaplan-Meier survival curves for patients with recurrent glioblastoma treated with cediranib. Note that the patients whose tumor perfusion increased survived longer than the rest. Data adapted.
Fig 4.
Fig 4.
(A) Normalization window is dose dependent; the higher the dose, the shorter the window. Higher doses can also lead to adverse effects in normal tissues. Data adapted. (B) Vascular normalization can convert the immunosuppressive microenvironment of a tumor to an immunostimultaory microenvironment and improve the outcome of various immunotherapies by increasing flow and oxygenation. Data adapted. TAM, tumor-associated macrophage.
Fig 5.
Fig 5.
(A, B) Functional lymphatic vessels are not detected within tumors with two different techniques. (A) Top panel shows functional lymphatic vessels (green) in a mouse tail. Bottom panel shows the functional lymphatic vessels are absent within a sarcoma growing a mouse tail, but they have a larger diameter in the tumor margin (arrows). Reproduced from. (B) Functional lymphatic vessels (blue) are present around a breast tumor grown orthotopically in a mouse, but they are absent within the tumor mass. Yellow-red indicates blood vessels. Reproduced from. (C) Unlike normal valves (left), the valves in the lymphatic vessels draining a tumor are malformed (right). Reproduced from. (D) Unlike normal contraction and valve (left), both are abnormal in a lymphatic vessel draining a tumor. Data adapted (unpublished data; Dr Shan Liao).
Fig 6.
Fig 6.
(A) Intravenously administered 90-nm liposomes—approximately the size of liposomal doxorubicin—were injected into tumor-bearing mice. These particles leaked out of some tumor vessels but did not move far from the vessel wall. Reproduced from. (B) Similarly, 150-nm viral particles injected into a tumor do not move far from the injection site. Reproduced from. (C, D) Losartan treatment for 2 weeks led to a dramatic decrease in collagen as well as (E) an increase in penetration and accumulation of 100-nm particles in collagen-rich tumors. (F) This, in turn, increased the efficacy of gene therapy and liposomal doxorubicin in desmoplastic tumors. Data adapted. HSV, herpes simplex virus.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vakoc BJ, Lanning RM, Tyrrell JA, et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med. 2009;15:1219–1223. - PMC - PubMed
    1. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med. 2001;7:987–989. - PubMed
    1. Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 2005;307:58–62. - PubMed
    1. Jain RK. Taming vessels to treat cancer. Sci Am. 2008;298:56–63. - PubMed
    1. Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071–1121. - PMC - PubMed

Publication types