ABSTRACT
INTRODUCTION: Clinical application of antiangiogenic therapy lacks direct visualization of therapy efficacy and vascular resistance. We aimed to establish molecular imaging during treatment with sunitinib using the fibronectin extradomain A specific small immunoprotein(SIP)-F8 in glioma. METHODS: Biodistribution analysis of F8-SIP-Alexa-555 was performed in SF126-glioma bearing or control mice (n = 23 and 7, respectively). Intravital microscopy(IVM) was performed on a microvascular level after 7 days (n = 5 per group) and subsequently after 6 days of sunitinib treatment (n = 4) or without (n = 2).Additionally, near infrared fluorescence(NIRF) imaging was established with F8-SIP-Alexa-750 allowing non-invasive imaging with and without antiangiogenic treatment in orthotopic tumors (n = 38 divided in 4 groups). MRI was used to determine tumor size and served as a reference for NIRF imaging. RESULTS: F8-SIP demonstrated a time and hemodynamic dependent tumor specific accumulation. A significantly higher vascular accumulation occurred with antiangiogenic treatment compared to untreated tumors enabling visualization of resistant tumor vessels by F8-SIP-mediated NIRF imaging. In orthotopic tumors, sunitinib reduced F8-SIP-Alexa-750 enrichment volume but not fluorescence intensity indicative of F8-SIP accumulation in fewer vessels. CONCLUSION: F8-SIP is highly tumor specific with time and hemodynamic dependent biodistribution. The higher vascular accumulation to remaining vessels enables molecular imaging and targeting of therapy resistant tumor vessels.
ABSTRACT
Angiogenesis is critical for oxygen and nutrient delivery to proliferating tumor cells. Therefore, as angiogenesis is required and vital for the tumor growth and metastasis. Antiangiogenic therapy is considered to be beneficial for tumor growth prevention due to starvation of tumor of oxygen and nutrients, but in some cases, the benefits are not permanent. Tyrosine kinase inhibitors and many other agents often target angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway. Although preclinical studies showed satisfactory outcomes in tumor growth inhibition, antiangiogenic therapy in the clinical setting may not be effective. The resistance observed in several tumor types through alternative angiogenic "escape" pathways contributes to restoration of tumor growth and may induce progression, enhancement of invasion, and metastasis. Therefore, activation of major compensatory angiogenic pathways, sustaining tumor angiogenesis during VEGF blockade contributing to the recurrence of tumor growth overcome antiangiogenic strategies. In this review, we summarize the novel mechanisms involved in evasive resistance to antiangiogenic therapies and represent different cancer types which have the ability to adapt to VEGF inhibition achieving resistance to antiangiogenic therapy through these adaptive mechanisms.
ABSTRACT
Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival not only by providing oxygen and nutrients for anabolism but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in treating several tumor types. Nevertheless, resistance to therapy emerges over time. In this review we discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, and we also provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients.
Subject(s)
Drug Resistance, Neoplasm , Neoplasms , Neovascularization, Pathologic , Angiogenesis Inhibitors/therapeutic use , Animals , Humans , Hypoxia/metabolism , Hypoxia/pathology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathologyABSTRACT
Several types of tumor are currently treated with antiangiogenic drugs. Unfortunately, most of these patients develop therapy resistance and succumb to the disease. Recently, a novel mechanism of resistance to antiangiogenics involving metabolic symbiosis of tumor cells has been described. Strategies to block resistance are emerging as a promising therapeutic approach.