Microenvironment and Lung Cancer

TME Field Component: Adjacent Histologically Normal-Appearing Epithelium

Slaughter et al. initially coined the term “field cancerization” in 1953 to describe the histologically normal-appearing tissue adjacent to a neoplastic lesion that displays molecular abnormalities often identical to those in the tumor. The concept was seemingly rediscovered more than four decades later, when investigators renewed the effort to define the molecular mechanisms precipitating the development of an array of epithelial malignancies, including lung cancer. In contrast to other common epithelial malignancies, there is not yet a clinical rationale to evaluate potential premalignant lesions in people at risk for lung cancer. Thus, carefully designed clinical investigations are required to harvest these clinical specimens that would not otherwise be collected from these individuals. Although knowledge regarding the molecular changes that occur in the airway in the setting of lung carcinogenesis is only fragmentary at present, it is generally accepted that there are alterations in the airway epithelium that mirror many of the changes seen in the primary lung tumor.

For example, in lung cancer, mutations in the Kirsten rat sarcoma viral oncogene homolog ( KRAS ) gene were described in nonmalignant histologically normal-appearing lung tissue adjacent to lung tumor. Moreover, loss of heterozygosity events were frequent in cells obtained from bronchial brushings of normal and abnormal lungs from patients undergoing diagnostic bronchoscopy and were detected in cells from the ipsilateral and contralateral lungs. Likewise, mutations in the epidermal growth factor receptor ( EGFR ) oncogene were reported in normal-appearing tissue adjacent to EGFR -mutant lung adenocarcinoma and also occurred at a higher frequency at sites more proximal to the adenocarcinomas than at more distant regions. Global mRNA and microRNA expression profiles were also described in the normal-appearing bronchial epithelium of healthy smokers, and a cancer-specific gene expression biomarker was developed from the mainstem bronchus that can distinguish smokers with and without lung cancer. In addition, modulation of global gene expression in the normal bronchial epithelium in healthy smokers was similar in the large and small airways, and the smoking-induced alterations were mirrored in the epithelia of the mainstem bronchus and the buccal and nasal cavities.

Kadara et al. advanced the field in 2013 with their investigation of the spatial and temporal molecular field of injury in individuals with early-stage nonsmall cell lung cancer (NSCLC), as determined by expression profiling of the large airways after definitive surgery. The normal airway epithelia were collected by endoscopic bronchoscopy brushings 12 months after surgical removal of the tumors, then every 12 months thereafter for up to 36 months. Although the study had key limitations, gene networks mediated by the phosphoinositide 3-kinase ( PI3K ) and ERK gene networks were upregulated in the airways adjacent to the resected tumor, suggesting that PI3K pathway dysregulation in the field of cancerization represents an early event in lung carcinogenesis that may persist even after resection of the primary tumor. In a follow-up study, the same researchers performed expression profiling of multiple normal-appearing airways various distances from tumors in conjunction with paired NSCLC tumors and normal lung tissues that were still in situ at the time of airway epithelial cell collection. Site-independent profiles, as well as gradient and localized airway expression patterns, characterized the adjacent airway field of cancerization, suggesting they may be useful for distinguishing the large airways of people with lung cancer from those of cancer-free smokers. Such studies of the field of cancerization enrich our understanding of the molecular pathogenesis of lung cancer and have transformative clinical potential. Biomarker signatures within the field could be used for risk assessment, diagnosis, monitoring progression of disease during active surveillance, and predicting the efficacy of adjuvant therapies following surgery.

TME Cellular and Soluble Components: Immune Effector Cells and Cell-Secreted Inflammatory Mediators

Since the early 2000s, the authors of gene expression profiling studies of several tumor types have described molecular signatures associated with carcinogenesis and progression. The molecular signatures that emerged from the original gene sets were composed mainly of cytokine genes involved in immune and inflammatory responses. In a seminal study by Bhattacharjee et al. in 2001, microarray-based expression profiling of resected tumor specimens allowed the investigators to discriminate between biologically distinct subclasses of adenocarcinomas, as well as primary lung adenocarcinomas and metastases of nonlung origin. Soon thereafter, Beer et al. used expression profiling to predict survival among patients with early-stage lung adenocarcinomas. Likewise, an mRNA expression profile developed by Potti et al. identified a subset of patients with early-stage NSCLC at high risk of recurrence. More recently, to inquire whether gene expression changes in the noncancerous tissue surrounding tumors could be used as a biomarker to predict cancer progression and prognosis, Seike et al. conducted a molecular profiling study of paired noncancerous and tumor tissues from patients with adenocarcinoma. Many of the genes identified were part of an immune and inflammatory response signature previously reported in other cancers, but a unique subset of the genes was also predictive of lymph node status and disease prognosis among patients with NSCLC. Together, these studies provided the earliest indication of the potential for expression profiling and clear evidence that molecular signatures composed mainly of immune- and inflammation-related cytokines characterizing the cellular and soluble components of the TME correlate with important clinical parameters.