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The lung microenvironment: an important regulator of tumour growth and metastasis

Nature Reviews Cancer volume 19, pages 9–31 (2019)Cite this article

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Abstract

Lung cancer is a major global health problem, as it is the leading cause of cancer-related deaths worldwide. Major advances in the identification of key mutational alterations have led to the development of molecularly targeted therapies, whose efficacy has been limited by emergence of resistance mechanisms. US Food and Drug Administration (FDA)-approved therapies targeting angiogenesis and more recently immune checkpoints have reinvigorated enthusiasm in elucidating the prognostic and pathophysiological roles of the tumour microenvironment in lung cancer. In this Review, we highlight recent advances and emerging concepts for how the tumour-reprogrammed lung microenvironment promotes both primary lung tumours and lung metastasis from extrapulmonary neoplasms by contributing to inflammation, angiogenesis, immune modulation and response to therapies. We also discuss the potential of understanding tumour microenvironmental processes to identify biomarkers of clinical utility and to develop novel targeted therapies against lung cancer.

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Fig. 1: The heterogeneous microenvironment of the lung.
Fig. 2: The heterogeneous microenvironment of lung cancer.
Fig. 3: Cancer cell-intrinsic pathways mediate immunosuppression in lung cancer.
Fig. 4: The lung metastatic niche.

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Acknowledgements

The authors thank B. Sleckman, G. Koretzky and J. Cubillos-Ruiz for reading the manuscript and providing insights. They also thank S. Lee for editing this manuscript and Y. Ban and R. Shaykhiev for help with figures. The authors acknowledge funding support from US National Institutes of Health (U01 CA188388), US Department of Defense and Meyer Cancer Center Pilot grants. The authors apologize for being unable to include several excellent studies owing to space limitations.

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA

    Nasser K. Altorki, Geoffrey J. Markowitz, Dingcheng Gao, Jeffrey L. Port, Brendon Stiles, Timothy McGraw & Vivek Mittal

  2. Neuberger Berman Foundation Lung Cancer Research Center, Weill Cornell Medicine, New York, NY, USA

    Nasser K. Altorki, Geoffrey J. Markowitz, Dingcheng Gao, Jeffrey L. Port, Brendon Stiles & Vivek Mittal

  3. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Nasser K. Altorki, Dingcheng Gao, Jeffrey L. Port, Ashish Saxena, Brendon Stiles, Timothy McGraw & Vivek Mittal

  4. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA

    Dingcheng Gao & Vivek Mittal

  5. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Ashish Saxena

  6. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA

    Timothy McGraw

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Contributions

N.K.A. and V.M. researched the data for the article and contributed to the writing of the article. V.M. reviewed and edited the manuscript before submission. A.S., B.S. and J.L.P. contributed to the clinical components of the manuscript. G.J.M. researched and organized all the information on the tumour microenvironment (TME) targets and clinical trials targeting the TME. D.G. and T.M. reviewed components related to the pre-metastatic niche and the tumour-intrinsic influence on the microenvironment.

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Correspondence to Vivek Mittal.

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Supplementary information

Supplementary Table 1

41568_2018_81_MOESM2_ESM.mov

Supplementary Movie 1 Panel A Time lapse movie showing two tumour cells (green) that have extravasated from the blood vessels into the parenchyma of the lung and interacting with macrophages (cyan). This interaction remains stable over extended periods of time and leads to the formation of tumor microenvironment of metastasis (TMEM) structures, openings for intravasation leading to haematogenous dissemination of tumour cells. Red = TMR labeled 155kD dextran, Green = E0771-GFP tumor cells, Cyan = CFP labeled macrophages

41568_2018_81_MOESM3_ESM.mov

Supplementary Movie 1 Panel B Time lapse video of lung metastatic tumour showing TMEM, consisting of a tumour cell, macrophage and endothelial cell in direct contact. Functional TMEM are the sites of transient vascular permeability and location of intravasation and haematogenous dissemination of tumour cells. Direct visualization of transient vascular leakage of TMR labeled 155kD dextran (red) from the serum into the interstitium at t=10 min indicates the adjacent TMEM is functional. Red = TMR labeled 155kD dextran, Green = E0771-GFP tumour cells, Cyan = CFP labeled macrophages. Images in panel A courtesy of D. Entenberg and J. Condeelis, Albert Einstein College of Medicine, New York. Panel B reproduced from Entenberg et al. Nat. Methods (2017)

Glossary

Aromatase

An enzyme responsible for the biosynthesis of oestrogen.

Chronic obstructive pulmonary disease

(COPD). A type of obstructive lung disease that includes chronic bronchitis and emphysema and is characterized by long-term breathing problems and poor airflow.

Desmoplasia

Excessive growth of fibrous or connective tissue around an invasive tumour.

Angiocrine signalling

Signalling that involves secreted and membrane-bound inhibitory and stimulatory growth factors, trophogens, chemokines, cytokines, extracellular matrix components, exosomes and other cellular products that are supplied by tissue-specific endothelial cells to help regulate homeostatic and regenerative processes in a paracrine or juxtacrine manner.

Degranulation

The process by which a cell releases the contents of its membrane-bound vesicles, called granules.

Tertiary lymphoid structures

(TLS). Transient ectopic lymphoid organizations that may develop after birth in non-lymphoid tissues in situations of chronic inflammation and cancer.

Doublet chemotherapy

A regimen of platinum compounds including cisplatin or carboplatin used as a standard of care in the management of advanced patients with non-small-cell lung cancer.

Immunogenic cell death

A form of cell death caused by, for example, cytostatic agents and radiation therapy that induces an effective antitumour immune response through activation of dendritic cells, which increase T cell priming.

Vascular co-option

A mechanism by which tumours obtain a blood supply from pre-existing vessels without undergoing angiogenesis. This is commonly observed in highly vascularized organs including the lungs and brain.

Cytometry by time of flight

(CyTOF). A variation of flow cytometry in which antibodies are labelled with heavy metal ion tags rather than fluorochromes. Readout is by time-of-flight mass spectrometry. This allows measurement of several cellular parameters in single samples without spectral overlap.

Radiomics

High-throughput mining of quantitative image features from standard of care medical imaging that enables data to be extracted and applied within clinical decision support systems to improve diagnostic, prognostic and predictive accuracy.

Radiopharmaceutical

The combination of a radioactive molecule, a radionuclide, that permits external detection and a biologically active molecule or drug that acts as a carrier and determines localization and biodistribution.

Rapid autopsy programmes

Programmes to arrange and perform autopsies on an urgent basis after death to collect tumour samples and other tissues for research purposes and clinical assessments.

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Altorki, N.K., Markowitz, G.J., Gao, D. et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer 19, 9–31 (2019). https://doi.org/10.1038/s41568-018-0081-9

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