VEGFR inhibition using sunitinib does not result in tumor

VEGFR2 inhibition using sunitinib does not result in tumor growth reduction or in a further decrease in vessel density in NDRG1 overexpressing glioma rendering these tumors intrinsically resistant to antiangiogenic treatment. Intrinsic resistance to antiangiogenic therapy is defined as a non-response [2]. The exact reason for this phenomenon cannot be assessed in detail in the present study. Our experimental approach does not allow for detailed analysis of synergistic, additive or antagonistic effects of TNFSF15 and sunitinib by isobologram, which investigates the interaction of two pure substances [44]. The cellular supernatant of NDRG1 overexpressing atomoxetine hcl does not purely consist of TNFSF15, but rather includes a cocktail of different cytokines, growth factors and signaling molecules (Supplementary Fig. S3). Consequently, the exact interaction of TNFSF15 and sunitinib is not addressed in our study. The molecular reasons underlying resistance to antiangiogenic therapy are very diverse [45]. Pericytes may induce vascular resistance to Sunitinib by altering Ang-1, Tie-2 and Dll4 expressions [4]. However, in the present study pericytes are not altered in NDRG1 overexpressing glioma. Other mechanisms include upregulation of alternative angiogenic pathways, modulation of the HIF sensor and response, induction of vessel cooption and recruitment of vascular accessory cells [46]. Which of these molecular and cellular mechanisms are altered cannot be answered by the data presented. Nevertheless, therapeutical implications for NDRG1 have been recently reported as NDRG1 mediates resistance to the alkylating agent temozolomide depending on MGMT [8], [47]. NDRG1 overexpressing gliomas are demonstrated to be resistant to antiangiogenic therapy. In the face of the lack of current markers or strategies to identify glioblastoma patients who benefit from antiangiogenic treatment, high NDRG1 expression may help to identify patients who do not respond to antiangiogenic therapy and therefore may contribute to personalized GB treatment.
Conflict of interest
Acknowledgments This work was supported within the Brain Tumor Network (BTNplus; Subproject 6) of the National Genome Research Network (NGFNplus) by the Federal Ministry of Education and Research (BMBF), the ‘Förderverein für Gehirntumorforschung Karlsruhe e.V.’, the Charitable Hertie Foundation and the Deutsche Forschungsgemeinschaft (SFB 938 TP K). T.B. received the Ernst von Leyden fellowship by the ‘Berliner Krebsgesellschaft e.V.’ and is a doctoral student of the PhD Program Medical Neuroscience of the Charité. J.B. and C.T. are doctoral students in the PhD Program of the DKFZ. M.C. was part of the Friedrich C. Luft Clinical Scientist Pilot Program funded by the Volkswagen Foundation and the Charité Foundation. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Introduction The growth of a malignant tumor is inevitably accompanied by microcirculatory network remodeling. From the beginning of tumor growth, blood capillaries are pushed away by actively proliferating tumor mass and are destroyed within it due to elevated mechanical pressure and various chemical factors, among which are increased acidity and alterations of angiopoietins expression (Araujo, McElwain, 2004, Holash, Maisonpierre, Compton, Boland, Alexander, Zagzag, Yancopoulos, Wiegand, 1999). This destruction along with inability of microcirculatory system to satisfy increased metabolic demands of neoplastic cells limit tumor growth rate and ultimately lead to metabolic stress in tumor core and subsequent necrosis formation therein. Tumor cells react to harsh conditions by inducing angiogenesis, i.e., the process of new blood vessels formation, which has been widely accepted as one of the major hallmarks of cancer (Hanahan and Weinberg, 2000). In normal conditions the process of angiogenesis takes place, e.g., during wound healing and embryonic development, and is subtly orchestrated by balanced action of pro- and antiangiogenic factors, resulting in fine-tuned well-functioning vascular system. However, sustained excessive production of antiangiogenic factors by tumor leads to formation of chaotic microvasculature with malformed capillaries, characterized by abnormal morphology of endothelial cells, lack of supporting pericytes and consequent alterations in form and functionality – these capillaries are dilated, tortuous and far more permeable for blood plasma and its solutes than normal continuous capillaries, which is the prevalent type of body microvessels (Fukumura, Jain, 2007, Maeda, Wu, Sawa, Matsumura, Hori, 2000).