**Author details**

neovascularization including vascular mimicry (VM) [138]. VM is identified as tumor cells, most likely GSCs, transdifferentiate into endothelial cells and form neovascular structures to irrigate the hypoxic tumors for both nutrients and active metabolism [139, 140]. GSCs also transdifferentiate into pericytes to maintain VM [141]. Thus, VM is one of the key tumorinherent mechanisms to drive the resistance to anti-angiogenesis therapy in GBM [142–144]. Indeed, resistance to RTK-targeted and combination therapies is associated with accumulation of GSC as well as immune suppression. Achyut et al. reported that vatalanib treatment increased the number of CD68+ myeloid cells and the CD133+, CD34+, and Tie2+ endothelial cell signatures in a mouse model of GBM [145]. The enhanced myeloid cell infiltration in the TME following therapeutic resistance was associated with the activation of the CSF1–CSF1R pathway, which results in increased number of tumor-associated macrophages (TAM) within

Collectively, the mechanisms of resistance to RTK-targeted therapy include (1) intratumoral heterogenicity of RTKs, that is, cooperation of various RTKs and their downstream signaling pathways; (2) intertumoral heterogenicity of RTK expression and activity within TME; (3) the treatment-induced shaping and adaption of TME including secondary hypoxia, accumulation of GSC and immune suppression [77]. These mechanisms may cause from ineffectiveness to treatment failure, or even clinical toxicity, leading to GBM recurrence. Moreover, during RTKtargeted treatment, most clinical studies actually lack sufficient information regarding the measurement on intratumoral drug levels, target engagement and the degree of inhibition on the targeted RTK in real time [82]. Nonetheless, design of further combination therapies should consider such information, in addition to monitoring the tumor dynamic profiles, and treat the patients according to the corresponsive patterns in disease progression. Therefore, understanding the biology of CNS tumors and influence of TME on tumor progression is becoming increasingly important for developing new therapeutic strategies for this deadly disease.

Not to mention intertumoral heterogeneity of the RTK expression, intratumoral heterogeneity, in particular the heterogeneity of amplified and mutated RTKs, presents a serious challenge to design successful single agent and/or combination therapies for patients with GBM. Thus far, clinical trials with small molecules kinase inhibitors still did not change the clinical practice in human malignant glioma [148]. GBM is one of the most challenging malignancies as featured with its infiltrating nature, recurrent tendencies and poor response to any treatment modalities, besides the intertumoral and intratumoral heterogeneity [31, 82]. The major treatment challenges contain aberrant signaling pathways, hypoxic microenvironment, phenotypic and genetic heterogeneity, GSCs and the blood-brain barrier (BBB) [1, 35, 82]. Nonetheless, aberrant RTK mutation and associated signaling pathways are hallmarks of primary GBM. As we show in this chapter, the functional interaction between RTKs and TME in GBM significantly promotes more aggressive tumor invasion, neovascularization and hypoxia, increases the number of GSCs, and adapts tumor metabolism. Thus, considering the importance of the TME

dynamic TME [146, 147].

42 Glioma - Contemporary Diagnostic and Therapeutic Approaches

**5. Conclusion and future perspectives**

Yujiao Gong1† , Yucui Dong1† , Jingru Cui<sup>1</sup> , Quanye Sun<sup>1</sup> , Ziqi Zhen<sup>1</sup> , Yifan Gao<sup>1</sup> , Jun Su<sup>2</sup> and Huan Ren<sup>1</sup> \*


2 Department of Neurosurgery, The 3rd Hospital Affiliated to Harbin Medical University, Harbin, China

† These authors contributed equally.
