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The Role of Tumor Microenvironment in Resistance to Anti-Angiogenic F1000Research 2018, 7(F1000 Faculty Rev):326 Last updated: 15 AUG 2018 REVIEW The role of tumor microenvironment in resistance to anti-angiogenic therapy [version 1; referees: 2 approved] Shaolin Ma 1,2, Sunila Pradeep1, Wei Hu1, Dikai Zhang2, Robert Coleman1, Anil Sood 1,3,4 1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2Reproductive Medicine Research Center, Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong province, China 3Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA First published: 15 Mar 2018, 7(F1000 Faculty Rev):326 (doi: Open Peer Review v1 10.12688/f1000research.11771.1) Latest published: 15 Mar 2018, 7(F1000 Faculty Rev):326 (doi: 10.12688/f1000research.11771.1) Referee Status: Abstract Invited Referees Anti-angiogenic therapy has been demonstrated to increase progression-free 1 2 survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a version 1 significant clinical problem. Over the last decade, several mechanisms have published been identified to decipher the emergence of resistance. There is a multitude of 15 Mar 2018 changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in F1000 Faculty Reviews are commissioned the TME in the development of resistance to anti-angiogenic therapy. These from members of the prestigious F1000 include preclinical models of emerging resistance, dynamic changes in hypoxia Faculty. In order to make these reviews as signaling and stromal cells during treatment, and novel strategies to overcome comprehensive and accessible as possible, resistance by targeting the TME. peer review takes place before publication; the Keywords referees are listed below, but their reports are tumor microenvironment, anti-angiogenic therapy, drug resistance, MET not formally published. signaling 1 Miguel Quintela-Fandino, CNIO-Spanish National Research Cancer Centre, Spain 2 Andrew Reynolds, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, UK Discuss this article Comments (0) Page 1 of 19 F1000Research 2018, 7(F1000 Faculty Rev):326 Last updated: 15 AUG 2018 Corresponding author: Anil Sood ([email protected]) Author roles: Ma S: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Pradeep S: Writing – Review & Editing; Hu W: Writing – Review & Editing; Zhang D: Writing – Review & Editing; Coleman R: Supervision, Writing – Review & Editing; Sood A: Conceptualization, Supervision, Writing – Review & Editing Competing interests: RLC has received grant funding from Genentech, Merck, Janssen, Clovis, AZ, and Abbvie and serves on the scientific steering committee as an investigator for Tesaro, Clovis, AZ, and Abbvie. AKS serves on the advisory board for Kiyatec and has received research funding from M-Trap. The other authors declare that they have no competing interests. Grant information: Portions of this work were supported by the National Institutes of Health (P50 CA217685, P50 CA098258, CA177909, and R35 CA209904), the Frank McGraw Memorial Chair in Cancer Research, the Ann Rife Cox Chair in Gynecology, the American Cancer Society Research Professor Award, and the Institutional Core Grant (CA16672) to the MD Anderson Cancer Center from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2018 Ma S et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Ma S, Pradeep S, Hu W et al. The role of tumor microenvironment in resistance to anti-angiogenic therapy [version 1; referees: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):326 (doi: 10.12688/f1000research.11771.1) First published: 15 Mar 2018, 7(F1000 Faculty Rev):326 (doi: 10.12688/f1000research.11771.1) Page 2 of 19 F1000Research 2018, 7(F1000 Faculty Rev):326 Last updated: 15 AUG 2018 Introduction stability and transcription of HIF-1α and consequently causes the Angiogenesis is well recognized as an important step in the dimerization of HIF-1α and HIF-1β to form HIF1. HIF1 can bind growth and progression of many tumor types1. Over the last to target genes and increase gene transcription9. 15 years, anti-angiogenic therapy has become an effective modal- ity for cancer therapy. Several vascular endothelial growth HIF-1α is a potent pro-angiogenic factor that has been associated factor/receptor (VEGF/R) inhibitors have been approved by the with the regulation of VEGF, stromal cell-derived factor 1 (SDF1), US Food and Drug Administration for various solid tumors, plasminogen activator inhibitor 1 (PAI1), angiopoietins (Ang-1 including metastatic colorectal cancer (mCRC), metastatic and -2), platelet-derived growth factor (PDGF), Tie2 receptor, renal cell cancer, metastatic gastric cancer, non-small-cell lung and matrix metalloproteinases (MMP-2 and -9)10,11. The expres- cancer, recurrent/metastatic cervical cancer, recurrent ovarian sion of HIF-1α is driven by hypoxia and mediated by histone cancer, and glioblastoma multiforme (GBM). Although improve- deacetylase (HDAC). Deacetylation by HDAC is a critical ments in objective response and progression-free survival (PFS) post-translational modification to HIF-1α signaling. Upregulation have been seen, the impact of anti-angiogenic therapy on patient of HDACs has been observed in response to increasing HIF-1α overall survival (OS) is limited (Table 1) because of a host of signaling under hypoxia12. A phase I clinical trial showed that factors, including the induction of resistance2. The modes of the addition of HDAC inhibitor abexinostat to pazopanib led to a resistance to angiogenesis inhibitors, mechanisms of acquired durable response in some patients who experienced progression or intrinsic resistance, and strategies for overcoming resistance during anti-VEGF therapy13. In addition, inhibiting HDACs have been discussed (see 3–5). Meanwhile, new mechanisms and can abrogate the expression of HIF-1α protein in hypoxic therapies for anti-angiogenic resistance have emerged over the conditions and there is an additive or synergistic effect between last 3–5 years. Evidence suggests that changes in the tumor HDAC and VEGFR inhibitors in resistant cancers12,14. In vitro microenvironment (TME) play a critical role in such adaptation6. and in vivo data have demonstrated that nucleus accumbens- This review focuses mainly on the role of the TME in response associated protein-1 (NAC1), a critical molecule in promoting and resistance to anti-angiogenic therapy (Figure 1), and novel glycolysis under hypoxia, mediates glycolysis via HDAC4- strategies to overcome resistance by targeting the TME are also mediated stabilization of HIF-1α. The knockdown of NAC1 discussed. exhibits anti-tumor effects of bevacizumab, which means that NAC1 may be involved in resistance to anti-angiogenic The role of hypoxia in resistance to anti-angiogenic therapy15. Thus, NAC1-HDAC4-HIF-1α signaling might be an therapy important pathway in regulating resistance under hypoxia. Previous studies have shown that resistance to anti-angiogenic therapy is associated with hypoxia-induced alterations, VEGF- MET signaling independent cytokine-driven endothelial growth, mobilization HIF-1α can also regulate the c-MET/HGF pathway, which can of bone marrow-derived pro-angiogenic hematopoietic cells or induce tumor angiogenesis through stimulation of endothelial endothelial progenitors, and vessel co-option2–5,7. Anti-angiogenic cell (EC) proliferation, migration, and tubulogenesis16. Hypoxia therapy inhibits tumor growth effectively by reducing vessel enhances c-MET/HGF signaling by activating HIF-1α in several density; however, the subsequent expression of hypoxia-inducible types of cancers such as lung, ovarian, and cervical cancers17. factors (HIFs) and the responsive genes (for example, VEGF, MET and VEGFR pathways share common downstream mol- VEGFR, carbonic anhydrase [CA] IX, and CAXII) can lead to ecules such as mitogen-activated protein kinase (MAPK), ERK, therapeutic resistance8. In recent years, there has been growing AKT, and focal adhesion kinase (FAK), and the activation of evidence that hypoxia-triggered overexpression of HIF subunits c-MET/HGF might lead to the activation of VEGFR signaling. and the activated downstream pathways play a critical role in It has been shown that MET enhances the expression of VEGFA resistance to anti-angiogenic therapy. by interacting with src homology 2 domain containing and suppressing angiogenesis suppressor thrombospondin118. Other Role of HIF-1α in anti-angiogenic therapy studies have also demonstrated that MET contributes to resist- There are three α subunits (HIF-1α, -2α, and -3α) and one β subu- ance to VEGF(R) inhibitors via the activation of ERK–MAPK nit in the HIF family. HIF-1α is the oxygen-regulated subunit that and PI3K–AKT
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