Hypoxic resistance is the main obstacle to radiotherapy for laryngeal carcinoma. Our previous study indicated that hypoxia-inducible factor 1α (HIF-1α) and glucose transporter 1 (Glut-1) double knockout reduced tumour biological behaviour in laryngeal carcinoma cells. However, their radioresistance mechanism remains unclear. In this study, cell viability was determined by CCK8 assay. Glucose uptake capability was evaluated by measurement of ¹⁸ F-fluorodeoxyglucose radioactivity. A tumour xenograft model was established by subcutaneous injection of Tu212 cells. Tumour histopathology was determined by haematoxylin and eosin staining, immunohistochemical staining, and TUNEL assays. Signalling transduction was evaluated by Western blotting. We found that hypoxia induced radioresistance in Tu212 cells accompanied by increased glucose uptake capability and activation of the PI3K/Akt/mTOR pathway. Inhibition of PI3K/Akt/mTOR activity abolished hypoxia-induced radioresistance and glucose absorption. Mechanistic analysis revealed that hypoxia promoted higher expressions of HIF-1α and Glut-1. Moreover, the PI3K/Akt/mTOR pathway was a positive mediator of HIF-1α and/or Glut-1 in the presence of irradiation. HIF-1α and/or Glut-1 knockout significantly reduced cell viability, glucose uptake and PI3K/Akt/mTOR activity, all of which were induced by hypoxia in the presence of irradiation. In vivo analysis showed that knockout of HIF-1α and/or Glut-1 also inhibited tumour growth by promoting cell apoptosis, more robustly compared with the PI3K inhibitor wortmannin, particularly in tumours with knockout of both HIF-1α and Glut-1. HIF-1α and/or Glut-1 knockout also abrogated PI3K/Akt/mTOR signalling transduction in tumour tissues, in a manner similar to wortmannin. HIF-1α and/or Glut-1 knockout facilitated radiosensitivity in laryngeal carcinoma Tu212 cells by regulation of the PI3K/Akt/mTOR pathway.

Complex molecular and metabolic phenotypes depict cancers as a constellation of different diseases with common themes. Precision imaging of such phenotypes requires flexible and tunable modalities capable of identifying phenotypic fingerprints by using a restricted number of parameters while ensuring sensitivity to dynamic biological regulation. Common phenotypes can be detected by in vivo imaging technologies, and effectively define the emerging standards for disease classification and patient stratification in radiology. However, for the imaging data to accurately represent a complex fingerprint, the individual imaging parameters need to be measured and analysed in relation to their wider spatial and molecular context. In this respect, targeted palettes of molecular imaging probes facilitate the detection of heterogeneity in oncogene-driven alterations and their response to treatment, and lead to the expansion of rational-design elements for the combination of imaging experiments. In this Review, we evaluate criteria for conducting multiplexed imaging, and discuss its opportunities for improving patient diagnosis and the monitoring of therapy.

The tumor immune response is in a dynamic balance between antitumor mechanisms, which serve to decrease cancer growth, and the protumor inflammatory response, which increases immune tolerance, cell survival, and proliferation. Hypoxia and expression of HIF-1α and HIF-2α are characteristic features of all solid tumors. HIF signaling serves as a major adaptive mechanism in tumor growth in a hypoxic microenvironment. HIFs represent a critical signaling node in the switch to protumorigenic inflammatory responses through recruitment of protumor immune cells and altered immune cell effector functions to suppress antitumor immune responses and promote tumor growth through direct growth-promoting cytokine production, angiogenesis, and ROS production. Modulating HIF function will be an important mechanism to dampen the tumor-promoting inflammatory response and inhibit cancer growth.