Perivascular nitric oxide gradients normalize tumor vasculature

Kashiwagi, Satoshi; Tsukada, Kosuke; Xu, Lei; Miyazaki, Junichi; Kozin, Sergey V.; Tyrrell, James; Sessa, William C.; Gerweck, Leo E.; Jain, Rakesh K.; Fukumura, Dai

doi:10.1038/nm1730

Cited by 165 publications

(116 citation statements)

References 13 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…to total amount, are critical to its ultimate function (16,29). Under physiological conditions, eNOS produces NO in lymphatic endothelial cells at specific locations and times during a contraction cycle (22), which facilitates diastolic filling.…”

Section: Discussionmentioning

confidence: 99%

Impaired lymphatic contraction associated with immunosuppression

Liao

Cheng

Conner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

263

321

View full text Add to dashboard Cite

To trigger an effective immune response, antigen and antigen-presenting cells travel to the lymph nodes via collecting lymphatic vessels. However, our understanding of the regulation of collecting lymphatic vessel function and lymph transport is limited. To dissect the molecular control of lymphatic function, we developed a unique mouse model that allows intravital imaging of autonomous lymphatic vessel contraction. Using this method, we demonstrated that endothelial nitric oxide synthase (eNOS) in lymphatic endothelial cells is required for robust lymphatic contractions under physiological conditions. By contrast, under inflammatory conditions, inducible NOS (iNOS)-expressing CD11b + Gr-1 + cells attenuate lymphatic contraction. This inhibition of lymphatic contraction was associated with a reduction in the response to antigen in a model of immune-induced multiple sclerosis. These results suggest the suppression of lymphatic function by the CD11b + Gr-1 + cells as a potential mechanism of self-protection from autoreactive responses during on-going inflammation. The central role for nitric oxide also suggests that other diseases such as cancer and infection may also mediate lymphatic contraction and thus immune response. Our unique method allows the study of lymphatic function and its molecular regulation during inflammation, lymphedema, and lymphatic metastasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Impaired lymphatic contraction associated with immunosuppression

Liao

Cheng

Conner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

263

321

View full text Add to dashboard Cite

show abstract

“…As discussed below, many studies testing the effects of antiangiogenic drugs have shown a presence of a "normalization window"-a time period beginning with the appearance of a normalized vascular phenotype (typically within 1 -2 days of starting treatment), and ending when features of normalization are lost Winkler et al 2004;Jain 2005b;Batchelor et al 2007;Kamoun et al 2009 Xian et al 2006;McCarty et al 2007;Mazzone et al 2009. c This is controversial given recent reports of increased metastasis after antiangiogenic therapy in certain animal models (Ebos et al 2009;Paez-Ribes et al 2009 Gorski et al 1999;Hansen-Algenstaedt et al 2000;Lee et al 2000;Kozin et al 2001;Ader et al 2003;Winkler et al 2004;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006a;Dings et al 2007;Kashiwagi et al 2008;Batra et al 2009;Cerniglia et al 2009;Tsukada et al 2009;McGee et al 2010. g Teicher et al 1995a,b;Wildiers et al 2003;Segers et al 2006;Dickson et al 2007a,b,c;Bhattacharya et al 2008Bhattacharya et al , 2009Zhou et al 2008;Juan et al 2009;Zhou and Gallo 2009;J Liu, S Liao, B Diop-Frimpong, et al, unpubl. data. section, we discuss the key molecules implicated in tumor vessel biology with a focus on their role in regulating vascular normalization.…”

Section: Evidence For Vascular Normalization In Tumors Preclinical Evmentioning

confidence: 99%

“…Lee et al 2000;Winkler et al 2004;Dings et al 2007;Fischer et al 2007;Eichhorn et al 2008;Batra et al 2009;Skuli et al 2009;McGee et al 2010. j Teicher et al 1995bJain et al 1998;Bernsen et al 1999;Cohen-Jonathan et al 2001;Delmas et al 2003;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006b;Segers et al 2006;Cerniglia et al 2009;Qayum et al 2009;Cham et al 2010. k Ader et al 2003;Hamzah et al 2008;Kashiwagi et al 2008;Stockmann et al 2008;Maione et al 2009;Mazzone et al 2009;Skuli et al 2009;Tsukada et al 2009;Rolny et al 2011. l Yuan et al 1996Lee et al 2000;Wildiers et al 2003;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Kurozumi et al 2007;Taguchi et al 2008;Zhou et al 2008;Kamoun et al 2009;Ohta et al 2009;Gallo 2009. m Jain et al 1998;Izumi et al 2002;…”

Section: Vegfunclassified

“…j Teicher et al 1995bJain et al 1998;Bernsen et al 1999;Cohen-Jonathan et al 2001;Delmas et al 2003;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006b;Segers et al 2006;Cerniglia et al 2009;Qayum et al 2009;Cham et al 2010. k Ader et al 2003;Hamzah et al 2008;Kashiwagi et al 2008;Stockmann et al 2008;Maione et al 2009;Mazzone et al 2009;Skuli et al 2009;Tsukada et al 2009;Rolny et al 2011. l Yuan et al 1996Lee et al 2000;Wildiers et al 2003;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Kurozumi et al 2007;Taguchi et al 2008;Zhou et al 2008;Kamoun et al 2009;Ohta et al 2009;Gallo 2009. m Jain et al 1998;Izumi et al 2002;Ansiaux et al 2005;Salnikov et al 2005;Bhattacharya et al 2008Bhattacharya et al , 2009Schnell et al 2008;Cerniglia et al 2009. n Dickson et al 2007c;Kashiwagi et al 2008;di Tomaso et al 2009;…”

Section: Vegfunclassified

“…These include the EC-specific integrins (Friedlander et al 1995;Kurozumi et al 2007;Skuli et al 2009;Desgrosellier and Cheresh 2010;Primo et al 2010), semaphorins (Bielenberg et al 2006;Maione et al 2009), members of the nitric oxide synthase family (Kashiwagi et al 2005(Kashiwagi et al , 2008Yu et al 2005), TGF-b (Liu et al, submitted for publication), and interferon-b (Dickson et al 2007a,c;Taylor et al 2008). In keeping with the notion that it is the balance between pro-and antiangiogenic stimuli that moderates the equilibrium between normal and abnormal vessels, modulation of the activity of these molecules is able to normalize tumor vessels structurally and/or functionally in a variety of tumor models preclinically.…”

Section: Other Angiogenic Moleculesmentioning

confidence: 99%

See 2 more Smart Citations

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

Goel

Wong

Jain

2011

Cold Spring Harbor Perspectives in Medicine

296

267

View full text Add to dashboard Cite

Pathological angiogenesis-driven by an imbalance of pro-and antiangiogenic signaling-is a hallmark of many diseases, both malignant and benign. Unlike in the healthy adult in which angiogenesis is tightly regulated, such diseases are characterized by uncontrolled new vessel formation, resulting in a microvascular network characterized by vessel immaturity, with profound structural and functional abnormalities. The consequence of these abnormalities is further modification of the microenvironment, often serving to fuel disease progression and attenuate response to conventional therapies. In this article, we present the "vascular normalization" hypothesis, which states that antiangiogenic therapy, by restoring the balance between pro-and antiangiogenic signaling, can induce a more structurally and functionally normal vasculature in a variety of diseases. We present the preclinical and clinical evidence supporting this concept and discuss how it has contributed to successful treatment of both solid tumors and several benign conditions.

show abstract

Nitric Oxide‐Based Nanomedicines for Conquering TME Fortress: Say “NO” to Insufficient Tumor Treatment

Xiang,

Chen,

Nan

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

Almost all cancer treatments are significantly limited by the strong tumor microenvironment (TME) fortress formed by abnormal vasculature, dense extracellular matrix (ECM), multidrug resistance (MDR) system, and immune “cold” environment. In the huge efforts of dismantling the TME fortress, nitric oxide (NO)‐based nanomedicines are increasingly occupying a central position and have already been identified as super “strong polygonal warriors” to dismantle TME fortress for efficient cancer treatment, benefiting from NO's unique physicochemical properties and extremely fascinating biological effects. However, there is a paucity of systematic review to elaborate on the progress and fundamental mechanism of NO‐based nanomedicines in oncology from this aspect. Herein, the key characteristics of TME fortress and the potential of NO in reprogramming TME are delineated and highlighted. The evolution of NO donors and the advantages of NO‐based nanomedicines are discussed subsequently. Moreover, the latest progress of NO‐based nanomedicines for solid tumors is comprehensively reviewed, including normalizing tumor vasculature, overcoming ECM barrier, reversing MDR, and reactivating the immunosuppression TME. Lastly, the prospects, limitations, and future directions on NO‐based nanomedicines for TME manipulation are discussed to provide new insights into the construction of more applicable anticancer nanomedicines.

show abstract

Perivascular nitric oxide gradients normalize tumor vasculature

Cited by 165 publications

References 13 publications

Impaired lymphatic contraction associated with immunosuppression

Impaired lymphatic contraction associated with immunosuppression

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

Nitric Oxide‐Based Nanomedicines for Conquering TME Fortress: Say “NO” to Insufficient Tumor Treatment

Contact Info

Product

Resources

About