Tumor Signaling and Angiogenesis

Therapy resistance is an emerging hallmark and daunting outcome for any adjuvant treatment in the clinic, for example (1) targeting tumor cells through chemotherapies, (2) targeting endothelial cells through anti-angiogenic treatments, or (3) improving anti-tumor immunity through immune-therapies. Most of the adjuvant treatments have witnessed involvement of bone marrow derived cells, causing therapy resistance and tumor relapse in a subset of patients. 

Our laboratory is devoted to determining the mechanisms of therapy resistance by focusing on the involvement of bone marrow derived cells in modulating the tumor microenvironment and initiating tumor neovascularization in glioblastoma and breast cancer models. To understand the involvement of bone marrow cells in developing resistance to antiangiogenic therapies (AAT), our group has developed chimeric animal models where bone marrow of the recipient animal is replaced with GFP+ bone marrow. The accumulation of GFP+ bone marrow cells can be determined by in vivo optical imaging. Our group documented that tumor-recruited bone marrow cells are a predominantly heterogeneous myeloid cell population that is able to predict therapeutic response in cancer. Therefore, we are using several strategies to target bone marrow or tumor-promoting myeloid cells to potentiate the anti-tumor effect of FDA-approved drugs in preclinical models of glioblastoma and breast cancer. In addition, our group has successfully tested IV formulation of the new drug HET0016 for the treatment of glioblastoma and breast cancers. 

In addition to the tumor cell extrinsic mechanisms, tumor intrinsic mechanisms such as vascular mimicry are being actively investigated in our laboratory. Tumor cells, under the influence of therapeutic drugs, acquire endothelial cell-like characteristics through a mesenchymal cell state to enhance tumor vasculature and therapy resistance to cause relapse. We have identified a possible pathway that governs the transdifferentiation of tumor cells to make their own blood-supplying channels in the case of AAT-induced hypoxia. Our group also identified that following anti-angiogenic treatment there is nuclear translocation of VEGFR2 in glioma.

My research interest is to understand development of alternative neovascularization in tumors following anti-angiogenic therapies in glioblastoma and breast cancers. I investigate the effects of different antiangiogenic agents in glioblastoma and breast cancers and try to understand whether targeting tumor microenvironment associated cells would be a better option to counter the therapy resistance in glioblastoma and breast cancers. In addition, my laboratory also investigates the mechanisms of cell-to-cell interaction by means of exosomes, and we have generated engineered exosomes as imaging and therapeutic probes to target immune-suppressive cells in tumor microenvironment.


 Zhang L, Wang Y, Rashid MH, Liu M, Angara K, Mivechi NF, Maihle NJ, Arbab AS, Ko L. Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis. Oncotarget 2017 (accepted)

Angara K, Borin TF, Arbab AS. Vascular Mimicry: A novel neovascularization mechanisms driving anti-angiogenic therapy (AAT) resistance in glioblastoma. Trans Oncol. 2017 (in press)

Ouzounova M, Lee E, Piranlioglu R, El Andaloussi A, Kolhe R, et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat Commun. 2017 Apr 6;8:14979. PubMed PMID: 28382931. doi: 10.1038/ncomms14979

Achyut BR, Arbab AS. Taming immune suppressor: application of myelid-derived suppressor cells in anti-cancer gene therapy. Translational Cancer Research 2017;6:S160-S162.

Iqbal S, Rashid MH, Arbab AS, Khan M. Encapsulation of anticancer drugs (5-fluorouracil and paclitaxel) into polycarprolactone (PCL) nanofibers and in vitro testing for sustained and targeted therapy. J Biomed Nanotech. 2017;13:355-366. doi:10.1166/jbn.2017.2353

Jain M, Gamage NH, Alsulami M, Shankar A, Achyut BR, et al. Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models. Sci Rep. 2017 Jan 31;7:41809. PubMed PMID: 28139732; PubMed Central PMCID: PMC5282583.

Angara K, Rashid MH, Shankar A, Ara R, Iskander A, et al. Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies. Histol Histopathol. 2016 Dec 19;PubMed PMID: 27990624.

Arbab AS, Jain M, Achyut BR. p53 Mutation: Critical Mediator of Therapy Resistance against Tumor Microenvironment. Biochem Physiol. 2016 Oct;5(3)PubMed PMID: 27917327; NIHMSID: NIHMS829471; PubMed Central PMCID: PMC5135095.

Zhang L, Varma NR, Gang ZZ, Ewing JR, Arbab AS, et al. Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle. J Nanomed Nanotechnol. 2016 Oct;7(5)PubMed PMID: 28018751; NIHMSID: NIHMS829446; PubMed Central PMCID: PMC5180609.

Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, et al. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res. 2016 Apr 15;76(8):2076-81. PubMed PMID: 26964621; NIHMSID: NIHMS778048; PubMed Central PMCID: PMC4873329.

Edhayan G, Ohara RA, Stinson WA, Amin MA, Isozaki T, et al. Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis. Arthritis Res Ther. 2016 Apr 12;18:87. PubMed PMID: 27071670; PubMed Central PMCID: PMC4830090.

Shankar A, Jain M, Lim MJ, Angara K, Zeng P, et al. Anti-VEGFR2 driven nuclear translocation of VEGFR2 and acquired malignant hallmarks are mutation dependent in glioblastoma. J Cancer Sci Ther. 2016;8(7):172-178. PubMed PMID: 28149448; NIHMSID: NIHMS795956; PubMed Central PMCID: PMC5279703.

Arbab AS, Jain M, Achyut BR. Cancer Therapeutics Following Newton's Third Law. Biochem Physiol. 2016;5(1)PubMed PMID: 28149704; NIHMSID: NIHMS795153; PubMed Central PMCID: PMC5279577.

Achyut BR, Arbab AS. Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther. 2016;9:1047-55. PubMed PMID: 27042097; PubMed Central PMCID: PMC4780185.

Shankar A, Borin TF, Iskander A, Varma NR, Achyut BR, et al. Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma. Onco Targets Ther. 2016;9:1205-19. PubMed PMID: 27022280; PubMed Central PMCID: PMC4790509.

Achyut BR, Shankar A, Iskander AS, Ara R, Knight RA, et al. Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments. Cancer Biol Ther. 2016;17(3):280-90. PubMed PMID: 26797476; PubMed Central PMCID: PMC4847989.

Shaaban S, Alsulami M, Arbab SA, Ara R, Shankar A, et al. Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. Int J Cancer Res. 2016;12(2):69-81. PubMed PMID: 27429653; NIHMSID: NIHMS749728; PubMed Central PMCID: PMC4945124.

Borin TF, Arbab AS, Gelaleti GB, Ferreira LC, Moschetta MG, et al. Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression. J Pineal Res. 2016 Jan;60(1):3-15. PubMed PMID: 26292662; NIHMSID: NIHMS796349; PubMed Central PMCID: PMC4996347.

Achyut BR, Shankar A, Iskander AS, Ara R, Angara K, et al. Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. Cancer Lett. 2015 Dec 28;369(2):416-26. PubMed PMID: 26404753; NIHMSID: NIHMS725121; PubMed Central PMCID: PMC4686232.

Bhuiyan MP, Aryal MP, Janic B, Karki K, Varma NR, et al. Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe. Contrast Media Mol Imaging. 2015 Nov-Dec;10(6):481-6. PubMed PMID: 26173742; NIHMSID: NIHMS706963; PubMed Central PMCID: PMC4713357.

Arbab AS, Jain M, Achyut BR. Vascular Mimicry: The Next Big Glioblastoma Target. Biochem Physiol. 2015 Sep;4(3)PubMed PMID: 27042399; NIHMSID: NIHMS725293; PubMed Central PMCID: PMC4814097.

Hou Y, Wu Y, Farooq SM, Guan X, Wang S, et al. A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis. Stem Cell Res. 2015 Mar;14(2):133-43. PubMed PMID: 25622052.

Jain M, Arbab AS, Achyut BR. When Seed and Soil Theory Meets Chicken or Egg Theory in Cancer Metastasis. Biochem Physiol. 2015 Feb 2;4(1)PubMed PMID: 26618093; NIHMSID: NIHMS704825; PubMed Central PMCID: PMC4662408.

Ferreira LC, Arbab AS, Jardim-Perassi BV, Borin TF, Varma NR, et al. Effect of Curcumin on Pro-angiogenic Factors in the Xenograft Model of Breast Cancer. Anticancer Agents Med Chem. 2015;15(10):1285-96. PubMed PMID: 25991545.

Verma VK, Kamaraju SR, Kancherla R, Kona LK, Beevi SS, et al. Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging. Int J Nanomedicine. 2015;10:711-26. PubMed PMID: 25653519; PubMed Central PMCID: PMC4309779.

Chwang WB, Jain R, Bagher-Ebadian H, Nejad-Davarani SP, Iskander AS, et al. Measurement of rat brain tumor kinetics using an intravascular MR contrast agent and DCE-MRI nested model selection. J Magn Reson Imaging. 2014 Nov;40(5):1223-9. PubMed PMID: 24421265; NIHMSID: NIHMS743001; PubMed Central PMCID: PMC4686270.

Books and Chapters

Achyut BR, Arbab AS. Cell Therapy for Brain Injury.. Hess DC, editor. New york: Springer; 2015. Chapter 12, Tracking of Administered Progenitor Cells in Brain Injury and Stroke by Magnetic Resonance Imaging.; p.187-212. 369p.

Kumar S, Ali MM, Arbab AS. Brain Tumor Imaging. 1st ed. Jain R, Essig M, editors. NY, USA: Thieme; 2015. On the Horizon: Molecular Imaging384p.

Arbab AS. Stem cells and cancer stem cells. hayat MA, editor. United States: Springer; 2013. CD34+/AC133+ EPCs as imaging probes for neovascularization of tumors323p.

Janic B, Arbab AS. The Synthesis, Surface Engineering and Cytotoxicity of Superparamagnetic Iron Oxide Nanoparticles for Bioengineering. 1st ed. Mahmoudi M, Stroeve P, Milan AS, Arbab AS, editors. Hauppauge, NY, USA: Nova Science Publishers, Inc.; 2011. Application of SPIONs. Superparamagnetic iron oxide nanoparticles

Arbab AS, Frank JA. Stem cell labeling for delivery and tracking using non-invasive imaging. 1st ed. Kraitchman DL, Wu JC, editors. Florida: CRC Press; 2011. Magnetic resonance imaging cell labeling methods

Arbab AS, Frank JA. Inorganic nanoprobes for biological sensing and imaging,. 1st ed. Mattoussi H, Cheon J, editors. Boston, USA: Artech House; 2008. Magnetic nanoparticles assisted cellular MR imaging and their biomedical applications; p.251-287.

Frank JA, Anderson SA, Arbab AS. Molecular and Cellular MR Imaging. Modo M, Bulte J, editors. Florida: CRC Press; 2007. Methods for labeling nanophagocytic cells with MR contrast agents; p.296-316.