Hypoxia in Lung Cancer Management

Hypoxia in Lung Cancer Management: Comparison

Please note this is a comparison between Version 2 by valérian dormoy and Version 1 by valérian dormoy.

Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice.

non-small cell lung cancer
hypoxia
HIF
angiogenesis
oxygen sensing
lung cancer management

Introduction

Lung cancer represents the leading cause of cancer-related deaths worldwide with 1.761 million deaths in 2018 and an incidence exceeding 2 million (11.6%), largely represented by non-small cell lung cancer (NSCLC) [1]. Lung cancer is diagnosed at a locally advanced or metastatic stage in most cases, leading to poor outcomes and no curative options [2]. In recent decades, many innovative strategies have been designed to improve patient survival rates, namely tyrosine kinase inhibitors (TKIs) of oncogenic alterations or immunotherapies [3]. On the one hand, personalised medicine has emerged from proof of concept to current applications in clinical lung cancer management, but only a limited population harbours molecular targetable alterations and can benefit from this approach [4]. On the other hand, immunotherapies are now largely employed but obtain labile response rates with fewer than 40% of responders among a selected population [5]. Unfortunately, relapse and resistance fatally occur despite specific and adapted strategies. Consequently, global age-standardised 5-year survival remains within the range of 10–20% and a limited increase of up to 5% has been observed [6], arguing the need to further refine and improve clinical lung cancer management.

Hypoxia has been explored specifically in the context of cancer and numerous reports have suggested its potential clinical relevance. The deprivation of optimal oxygen supply at the cellular, tissular, or organ level, is a common feature observed in various physiological and pathological conditions, such as foetal and organ development or interstitial lung disease, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension [7,8,9,10,11,12,13]. Moreover, hypoxia is considered a crucial factor in carcinogenesis [14,15]. Hypoxia appears to be a central key sensor at the forefront of major steps of cancer progression [16] including invasiveness, acquisition of stem cell properties [17], stimulation of angiogenesis and lymphangiogenesis [18], immune escape [19], radiotherapy sensibility, cell survival and resistance to apoptotic signals [20]. Angiogenesis and vasculogenesis are hallmarks of hypoxia-induced modifications [21], but the whole spectrum of molecular and cellular events including oxygen sensing and its signalling pathways are still only partially elucidated [22]. The majority of experimental investigations have been focusing on HIF-1α (hypoxia-inducible factor 1-alpha), the key transcriptional regulator of response to hypoxia [23].

Hypoxia has been identified as a key player in cancer progression and initiation in the context of breast cancer, endocrine tumours, brain tumours, or malignant haematopoiesis processes [24,25,26,27,28]. In this review, we discuss the potential relevance of considering and implementing hypoxia in clinical practice to improve personalised lung cancer management. We focus on NSCLC because of its higher frequency and extensive literature in the field of hypoxia, although some reports also highlight the potential involvement of oxygen starvation in small cell lung cancer [29] and malignant pleural mesothelioma [30].

We provide here the overview of our report:

2. Biological features associated with hypoxia in NSCLC

2.1. Hypoxia-inducible factor detection in whole tumour tissues

2.2. Tumour-initiating cells and hypoxic conditions

2.3. Tumour microenvironment features in hypoxic condition

2.4. Molecular signature of hypoxic tumours

3. Available tools to detect hypoxia in clinical practice

3.1. Hypoxic characterisation by imaging techniques

3.2. Circulating markers to help clinicians classify hypoxic tumours

3.3. Emerging approaches in hypoxic-tumour identification

4. Prognostic implications of hypoxia in lung cancer

4.1. Early and locally advanced stages

4.2. Metastatic stages: potential hypoxia-related treatment strategies, from response to resistance

5. Hypoxia-related treatments and research development

5.1. Pyruvate Dehydrogenase Kinase (PDK) inhibitors

5.2. Metformin

5.3. Vorinostat

5.4. Nitroglycerin

5.5. Tirapazamine

5.6. Efaproxiral

5.7. Anti-angiogenic therapies

6. Conclusions

In this study, we conducted an extensive review of the potential impact of hypoxia in each stage of NSCLC and highlighted clinical and pathological features related to hypoxic tumours relevant to clinicians. It appears that some tumours are more frequently associated with hypoxic regions than others, such as poorly differentiated SqCC presenting a tumour microenvironment including high tumoural microvessel density and stroma-enriched immune cells harbouring epithelial-to-mesenchymal polarization. The current challenge to identifying hypoxia remains the definition of relevant thresholds for markers discriminating hypoxic from non-hypoxic tumours. Pathological examinations and immunostainings are needed to validate further markers in paired and matched comparison studies. The identification of biological signatures based on nucleic acid expressions may contribute to the development of hypoxic-scores after validation in larger and design-dedicated cohorts. Systematic genetic association studies taking hypoxia as a relevant parameter will ideally complement the translational approach. We also reviewed current promising approaches allowing to evaluate hypoxia in the NSCLC context with a special interest in the most suitable and transposable approaches in clinical routine. Tumour hypoxia biology is complex and in constant evolution over time, given that sequential drugs and radiation use lead to resistance and treatment escape. We finally investigated how hypoxic characterisation could influence the major steps of lung cancer clinical management. For patients with early cured NSCLC, transversal hypoxic tumour determination might also be of interest to isolate and predict those who would benefit from adjuvant therapies to reduce the risk of relapse. Nonetheless, challenges and clinical goals are specific in advanced and metastatic stages when aiming to predict tumour response across various regimens of treatments. In these later stages, longitudinal hypoxic characterisation might be the most relevant approach. Repeated PET/CT scans and more strikingly, circulating hypoxia-related markers may enable monitoring of tumour variations and adaptation of clinical strategies in a personalised approach. Despite limitations to hypoxia implementation in lung cancer clinical management, evidence is accumulating for its consideration, including dedicated hypoxia-related treatments. Hypoxia characterisation could improve the outcome of patients with NSCLC and might represent the next step to a personalised medical protocol in the field of cancer.