Non-small-cell lung cancers: a heterogeneous set of diseases

Abstract

Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.

Figure 1. The lung cancer microenvironment

The tumour microenvironment, including endothelial cells, fibroblasts and myeloid cells, among others, has important roles in determining the characteristics of lung tumours. It is likely that a combination of the cell of origin, genetic alterations and microenvironmental factors all contribute to the lineage identity of lung tumours. Extracellular matrix (ECM), which often consists of keratins in lung squamous cell carcinoma and fibronectin in desmoplastic lung adenocarcinomas, gives structural support to tumour cells and is associated with tumour-associated fibroblasts. Blood vessels are newly formed at the tumour site by recruitment of endothelial cells via platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), among others. As the blood and lymphatic vessels form, numerous blood cells, including macrophages, neutrophils, T cells and B cells, home to the tumours. In particular, tumours can recruit neutrophils through secretion of CXC-chemokine ligand (CXCL) family members, which bind to the neutrophil receptor CXCR2. In addition, tumour cells often express immune checkpoint molecules, such as programmed cell death 1 ligand 1 (PDL1), to attenuate a cytotoxic response from T cells. PD1, programmed cell death 1.

Figure 2. A diagram of proximal and distal lung cells, indicating markers that are retained in carcinomas and putative squamous cell carcinoma (SCC) and adenocarcinoma (ADC) cells of origin

Diverse lung stem or progenitor cell populations are thought to have the ability to drive lung oncogenesis in different contexts. In the proximal lung, the tracheal basal cell has been proposed to be the cell of origin for lung SCC. The evidence for this relationship includes the expression of p63, SRY-box 2 (SOX2) and keratin 5 (KRT5) within the basal cells, squamous metaplasia of the basal cells (common in smokers), and squamous cell carcinomas. Squamous tumours are modelled in mice by Kras^G12D expression and liver kinase B1 (Lkb1) knockout (20% of lesions are squamous), knocking in a germline dominant-negative kinase-dead inhibitor of nuclear factor-κB kinase subunit-α (IKKα) and knocking out both Lkb1 and Pten (100% of lesions are squamous for the second two models). Two bronchiolar cell populations, the bronchiolar progenitor cells and the bronchioalveolar stem cells (BASCs) may also be able to give rise to tumours with squamous characteristics, although experimental lineage tracing is needed to confirm this theory. ADCs can be modelled by Kras^G12D expression (long latency), Kras^G12D expression and Trp53-null, and epidermal growth factor receptor (EGFR)^T790M/L858R, among other genetic models, and they are thought to arise from more proximal airway cells. These tumours often retain characteristics of proximal airways, such as the expression of surfactant protein C (SPC), KRT7 and thyroid transcription factor 1 (TTF1). Again, BASCs or bronchiolar progenitor cells, which are able to give rise to alveolar lineages after lung injury, may likewise be able to give rise to tumours with alveolar characteristics. AcTUB, acetylated tubulin; AT, alveolar epithelial type; CCSP, club cell secretory protein; CGRP, calcitonin gene-related peptide.