Vascular normalization in Rgs5-deficient tumours promotes immune destruction

Hamzah, Juliana; Jugold, Manfred; Kießling, Fabian; Rigby, Paul; Manzur, Mitali; Marti, Hugo H.; Rabie, Tamer Samah; Kaden, Sylvia; Gröne, Hermann Josef; Hämmerling, Günter J.; Arnold, Bernd; Ganss, Ruth

doi:10.1038/nature06868

Cited by 502 publications

(455 citation statements)

References 28 publications

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“…Because dual therapy normalizes the vasculature, TAMs in dual therapy-treated tumors are adapted to an antitumor phenotype, as shown in our companion manuscript, and thus are able to affect survival positively. However, additional interventions may be necessary to decrease the MDSCs and further activate cytotoxic T lymphocytes-for example by immune checkpoint inhibition-to enhance antitumor adaptive immunity further (30,62,63). Taken together, our data warrant further studies to assess the therapeutic potential of the anti-VEGF/Ang-2 combination with novel immunotherapeutics in GBM (51,64).…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Peterson

Kirkpatrick

Huang

et al. 2016

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

264

225

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Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

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Section: Discussionmentioning

confidence: 99%

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Peterson

Kirkpatrick

Huang

et al. 2016

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

264

225

View full text Add to dashboard Cite

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“…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

“…Already discussed in this article are the importance of Ang-1 and PDGFRb signaling in maintaining normalized vessels. More recently, the regulator of G-protein signaling 5 (Rgs5), a molecule involved in PVC differentiation and a specific marker of PVCs, has been implicated as a key mediator of vascular normalization (Hamzah et al 2008). Although the function of Rgs5 is poorly understood, tumors growing in Rgs5 2/2 mice have a normalized vasculature, showing reduced vessel diameter and structural irregularity, improved oxygenation, and less vessel permeability.…”

Section: Perivascular Cell Targetsmentioning

confidence: 99%

“…Although the function of Rgs5 is poorly understood, tumors growing in Rgs5 2/2 mice have a normalized vasculature, showing reduced vessel diameter and structural irregularity, improved oxygenation, and less vessel permeability. Moreover, adoptive transfer of activated immune cells into tumors of Rgs5 2/2 mice yields increased antitumor T lymphocyte trafficking and a significant improvement in mouse survival (Hamzah et al 2008).…”

Section: Perivascular Cell Targetsmentioning

confidence: 99%

“…Hypoxic tumor cells often show a more aggressive phenotype, activating oncogenes and passing through an "epithelial to mesenchymal transition" (EMT), which heightens their metastatic potential (DeClerck and Elble 2010). Moreover, the hostile microenvironment impairs the function of antitumor immune cells, the delivery of which into the tumor is also impaired (Hamzah et al 2008). Importantly, tumor response to therapy is also impacted.…”

Section: Vascular Abnormalities In Solid Tumorsmentioning

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

300

267

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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.

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TGFBI modulates tumour hypoxia and promotes breast cancer metastasis

Fico

Santamaria-Martínez

2020

Molecular Oncology

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Breast cancer metastasis is a complex process that depends on intrinsic characteristics of metastatic stem cells, but also on the particular microenvironment that supports their growth and modulates the plasticity of the system. In search for microenvironmental factors supporting cancer stem cell (CSC) growth and tumour progression to metastasis, we here investigated the role of the matricellular protein Transforming Growth Factor Beta Induced (TGFBI) in breast cancer. We crossed the MMTV-PyMT model of mammary gland tumourigenesis with a Tgfbi / mouse, and studied the CSC content of the tumours. We performed RNAseq on wt and ko tumours, and analysed the tumour vasculature and the immune compartment by IHC and FACS. The source of TGFBI expression was determined by qPCR and by bone marrow transplantation experiments. Finally, we performed in silico analyses using the METABRIC cohort to assess the potential prognostic value of TGFBI. We observed that deletion of Tgfbi led to a dramatic decrease in CSC content and lung metastasis. Our results show that lack of TGFBI resulted in tumour vessel normalisation, with improved vessel perfusion and decreased hypoxia, a major factor controlling CSCs and metastasis. Furthermore, human data

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Vascular normalization in Rgs5-deficient tumours promotes immune destruction

Cited by 502 publications

References 28 publications

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

TGFBI modulates tumour hypoxia and promotes breast cancer metastasis

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