The Microenvironment of Lung Cancer and Therapeutic Implications

Abstract

The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.

Inhibition of PAI‐1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer‐associated fibroblasts

“…A large number of studies showed that cancer stromal cells, such as inflammatory cells, endothelial cells and fibroblasts, induced resistance to chemotherapy in lung cancer. 25 In the stromal cells, fibroblasts have been reported to be a main player in this phenomenon. 4,26 In the present study, we revealed that PAI-1 inhibition limited the chemotherapy resistance through suppressing the MF characteristics of CAFs.…”

Clinicopathological and prognostic significance of regulatory T cells in patients with non-small cell lung cancer: A systematic review with meta-analysis

“…Non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung malignancies and the overall 5-year survival of patients with NSCLC remains approximately 15–20% [3, 4]. Although the driver mutations including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) have revolutionized the treatment and prognosis of NSCLC, it just focused on the cancer cell intrinsic properties [5, 6]. More and more recent studies have begun to investigate the prognostic and clinicopathological role of tumor microenvironment (TME) in NSCLC [7, 8].…”

“…In the past, it had been supposed that the tumorigenesis and failure of cancer immunotherapy was due to the insufficient activation of immune system. Recently, increasing evidence indicates that inhibitory function plays the crucial role in the TME [6, 9]. One of the most significant inhibitory components is the regulatory T cells (Tregs).…”

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…In this regard, tumor microenvironment induces immune suppression, reduces the efficacy of chemotherapy, and favors epithelial-to-mesenchymal transition (EMT) in the airways (type-II EMT, obliteration of small airways), which has recently emerged as a novel target for LC treatment (112). In line with this, a recent investigation showed that treatment of lung epithelial cells with CS extracts induced alveolar EMT through a cascade of biological mechanisms characterized by a rise in TGF-beta and Rac1/Smad2 signaling pathway (113).…”