Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels

Tumour recurrence frequently occurs after radiotherapy, but the characteristics, intratumoural localization and post-irradiation behaviour of radioresistant cancer cells remain largely unknown. Here we develop a sophisticated strategy to track the post-irradiation fate of the cells, which exist in perinecrotic regions at the time of radiation. Although the perinecrotic tumour cells are originally hypoxia-inducible factor 1 (HIF-1)-negative, they acquire HIF-1 activity after surviving radiation, which triggers their translocation towards tumour blood vessels. HIF-1 inhibitors suppress the translocation and decrease the incidence of post-irradiation tumour recurrence. For the first time, our data unveil the HIF-1-dependent cellular dynamics during post-irradiation tumour recurrence and provide a rational basis for targeting HIF-1 after radiation therapy

Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities

Stereotactic Robotic Body Radiotherapy for Patients With Unresectable Hepatic Oligorecurrence

Micro-Abstract We present our retrospective study of 42 patients treated for hepatic oligorecurrence with stereotactic body radiotherapy using the CyberKnife system (Accuray Inc). Besides reporting on acute and late toxicities, the influence of patient and lesion characteristics on local control, liver and distant progression-free survival, and overall survival were also investigated. Background The purpose of this study was to analyze local control (LC), liver progression-free survival (PFS), and distant PFS (DFS), overall survival (OS), and toxicity in a cohort of patients treated with stereotactic body radiotherapy (SBRT) with fiducial tracking for oligorecurrent liver lesions; and to evaluate the potential influence of lesion size, systemic treatment, physical and biologically effective dose (BED), treatment calculation algorithms and other parameters on the obtained results. Patients and Methods Unoperable patients with sufficient liver function had [18F]-fluorodeoxyglucose-positron emission tomography-computed tomography and liver magnetic resonance imaging to confirm the oligorecurrent nature of the disease and to further delineate the gross tumor volume (GTV). An intended dose of 45 Gy in 3 fractions was prescribed on the 80% isodose and adapted if risk-related. Treatment was executed with the CyberKnife system (Accuray Inc) platform using fiducials tracking. Initial plans were recalculated using the Monte Carlo algorithm. Patient and treatment data were processed using the Kaplan–Meier method and log rank test for survival analysis. Results Between 2010 and 2015, 42 patients (55 lesions) were irradiated. The mean GTV and planning target volume (PTV) were 30.5 cc and 96.8 cc, respectively. Treatments were delivered 3 times per week in a median of 3 fractions to a PTV median dose of 54.6 Gy. The mean GTV and PTV D98% were 51.6 Gy and 51.2 Gy, respectively. Heterogeneity corrections did not influence dose parameters. After a median follow-up of 18.9 months, the 1- and 2-year LC/liver PFS/DFS/OS were 81.3%/55%/62.4%/86.9%, and 76.3%/42.3%/52%/78.3%, respectively. Performance status and histology had a significant effect on LC, whereas age (older than 65 years) marginally influenced liver PFS. Clinical target volume physical dose V45 Gy > 95%, generalized equivalent uniform dose (a = −30) > 45 Gy and a BED (α/β = 10) V105 Gy > 96% showed statistically significant effect on the LC. Acute Grade 3 gastrointestinal (GI) and late Grade 2 GI and fatigue toxicity were found in 5% and 11% patients, respectively. Conclusion Favorable survival and toxicity results support the potential paradigm shift in which the use of SBRT in oligorecurrent liver disease could benefit patients with unresectable or resectable liver metastases. © 2017 Elsevier Inc