Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer.

Most solid tumors, such as head and neck cancers, feature a hypoxic microenvironment due to angiogenic dysregulation and the consequent disruption of their vascular network. Such nutrient-deprived environment can induce genomic changes in several tumor cell populations, conferring survival and proliferative advantages to cancer cells through immunosuppression, metabolic switches and enhanced invasiveness. These transcriptional changes, together with the selective pressure hypoxia exerts on cancer cells, leads to the propagation of more aggressive and stress-resistant subpopulations increasing therapy resistance and worsening patient outcomes. Although extensive preclinical and clinical studies involving hypoxia-targeted drugs have been performed, most of these drugs have failed late-stage clinical trials and only a few have managed to be implemented in clinical practice. Here, we provide an overview of three main strategies to target tumor hypoxia: HIF-inhibitors, hypoxia-activated prodrugs and anti-angiogenic agents; summarizing the clinical advances that have been made over the last decade. Given that most hypoxia-targeted drugs seem to fail clinical trials because of insufficient drug delivery, combination with anti-angiogenic agents is proposed for the improvement of therapy response via vascular normalization and enhanced drug delivery. Furthermore, we suggest that using novel nanoparticle delivery strategies might further improve the selectivity and efficiency of hypoxia-targeted therapies and should therefore be taken into consideration for future therapeutic design. Lastly, recent findings point out the relevance that hypoxia-targeted therapy is likely to have in head and neck cancer as a chemo/radiotherapy sensitizer for treatment efficiency improvement.

Heterogeneity of CEACAM5 in breast cancer.

CEACAM5 is overexpressed in many primary breast carcinomas. However, the exact role of CEACAM5 in breast cancer tumorigenesis remains unresolved. Here, we examined a repository of 110 cryopreserved primary breast carcinomas by immunohistochemistry to assess the distribution of CEACAM5 in tumor subtypes. The majority of estrogen receptor-positive and HER2-overexpressing tumors were CEACAM5-positive, whereas most of Triple-negative tumors were negative. Assessing sample sets of paired primary breast cancers and corresponding lymph node lesions from a total of 59 patients revealed a high correlation between primary tumor and lymph node with regard to CEACAM5-status. However, a notable subset of sample sets demonstrated intratumoral heterogeneity in the primary tumor, the metastatic lesion or both, suggesting that both CEACAM5-positive and -negative cells can play a role in tumor dissemination. When examining the consequence of expression of CEACAM5 in breast cancer cell lines in culture assays we found that CEACAM5-expressing cells were less invasive. In survival analysis, using cohort studies of breast cancer, expression of CEACAM5 predicted different clinical outcomes depending on molecular subtypes. Altogether, our analysis suggests that CEACAM5 plays a context-dependent role in breast cancer that warrants further investigation.