The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets

• Published in: Cancer treatment reviews Vol. 40; no. 4; pp. 558 - 566
• Main Authors: Wood, Steven L., Pernemalm, Maria, Crosbie, Philip A., Whetton, Anthony D.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.05.2014; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Communication - physiology; Chemotaxis; Hematology, Oncology and Palliative Medicine; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Metastasis; Metastatic niche; Micro-environment; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Organ-tropism; Pharmacology. Drug treatments; Pneumology; Stromal Cells - pathology; Tumor Microenvironment; Tumors; Tumors of the respiratory system and mediastinum; M1-MØ; N1-N; RANKL; MDSC; Lung cancer; RANK; Metastasis; CSC; MC; miRNA; MSC; Micro-environment; Metastatic niche; SCLC; AC; Organ-tropism; NSCLC; M2-N; M2-MØ; PTHrP; Chemotaxis; LCC; EMT; SCC; LC; NK; CXCL12/SDF1α; DC; M1-macrophage; receptor activator of nuclear factor κB-ligand; cancer stem cell; small cell lung cancer; N1-neutrophil; non-small cell lung cancer; receptor activator of nuclear factor κB; epithelial-to-mesenchymal transition; micro-RNA; dendritic cell; parathyroid hormone related peptide; M2-neutrophil; mast-cell; stromal derived factor-1α; natural killer cell; mesenchymal stem cell; M2-macrophage; adenocarcinoma; myeloid-derived suppressor cells; large cell carcinoma; squamous cell carcinoma; Tropism; Lung disease; Targeting; Respiratory disease; Targeted therapy; Cell microenvironment; Malignant tumor; Bronchopulmonary; Treatment; Bronchus disease; Environment; Advanced stage; Cancer; Organ
• ISSN: 0305-7372; 1532-1967; 1532-1967
• DOI: 10.1016/j.ctrv.2013.10.001

Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell–cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity.