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The Role of the ECM in Lung Cancer Dormancy and Outgrowth - PubMed

  • ️Wed Jan 01 2020

Review

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

Amelia L Parker et al. Front Oncol. 2020.

Abstract

The dissemination of tumor cells to local and distant sites presents a significant challenge in the clinical management of many solid tumors. These cells may remain dormant for months or years before overt metastases are re-awakened. The components of the extracellular matrix, their posttranslational modifications and their associated factors provide mechanical, physical and chemical cues to these disseminated tumor cells. These cues regulate the proliferative and survival capacity of these cells and lay the foundation for their engraftment and colonization. Crosstalk between tumor cells, stromal and immune cells within primary and secondary sites is fundamental to extracellular matrix remodeling that feeds back to regulate tumor cell dormancy and outgrowth. This review will examine the role of the extracellular matrix and its associated factors in establishing a fertile soil from which individual tumor cells and micrometastases establish primary and secondary tumors. We will focus on the role of the lung extracellular matrix in providing the architectural support for local metastases in lung cancer, and distant metastases in many solid tumors. This review will define how the matrix and matrix associated components are collectively regulated by lung epithelial cells, fibroblasts and resident immune cells to orchestrate tumor dormancy and outgrowth in the lung. Recent advances in targeting these lung-resident tumor cell subpopulations to prevent metastatic disease will be discussed. The development of novel matrix-targeted strategies have the potential to significantly reduce the burden of metastatic disease in lung and other solid tumors and significantly improve patient outcome in these diseases.

Keywords: dormancy; extracellular matrix; lung cancer; matrix-targeting; metastasis.

Copyright © 2020 Parker and Cox.

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Figures

FIGURE 1
FIGURE 1

The interaction of cancer cells with the extracellular matrix (ECM) in the lung regulates diverse intracellular signaling pathways to regulate cancer cell dormancy, proliferation and metastases in NSCLC. Multiple cell types within the lung generate and remodel the extracellular matrix (A). The composition of the ECM differs from the central airways and peripheral parenchyma where alveoli enable gas exchange, and is highly dysregulated in NSCLC (A). This ECM is composed of matrisomal proteins, factors that associate with these proteins as well as enzymes involved in remodeling this matrix (B). The posttranslational modification of ECM proteins and their interaction with each other ECM components determines the biomechanics of the tissue. ECM remodeling also releases growth factors and reveals cryptic sites within ECM components that are recognized by cells. Receptors on the cell membrane directly interact with specific ECM components and secreted factors (C) to activate diverse intracellular signaling programs that regulate the proliferative and metastatic characteristics of cancer cells (D). These signaling programs drive the transcription of cell cycle regulators, stem cell markers and genes involved in EMT, migration, invasion and immune activation to regulate tumor dynamics (E). In addition, these signaling programs activate the expression of ECM genes and ECM remodeling enzymes to drive further evolution of the tumor microenvironment (E). Dotted lines indicate indirect interactions. ATII, Type II pneumocyte; ATI, Type I pneumocyte.

FIGURE 2
FIGURE 2

The tumor microenvironment contributes to matrix remodeling that regulates tumor cell dormancy and outgrowth in NSCLC. (A) Cancer cells release TGFβ, PDGF, and FGF2, which activate fibroblasts to a myofibroblast state. Activated myofibroblasts in the tumor microenvironment produce increased amounts of collagen I, collagen IV, Tenascin C, Thrombospondin-2 as well as remodeling enzymes and signaling effectors such as CTGF and MMPs. The resulting increased matrix stiffness further activates fibroblasts in a TGFβ-dependent manner. Stromal cells expressing α11β1-integrin engage with this extracellular matrix to promote the proliferation, migration, invasion and survival of cancer cells in the tumor microenvironment. (B) The extracellular matrix components of the perivascular niche support dormancy in cancer cells. The sprouting vasculature produces TGFβ and periostin that promote cancer cell proliferation and metastatic potential. Endothelial cells of the sprouting vasculature also produce MMP14, which cleaves laminin 5 γ2 to release EGF-like fragments that activate EGF signaling in cancer cells. (C) Activated infiltrating macrophages secrete TGFβ into the tumor microenvironment to activate fibroblasts and TGFβ-dependent signaling in cancer cells. α4β1-Integrin-expressing macrophages engage with VCAM-1 expressing cancer cells to induce pro-survival Akt-PI3K signaling. Proteases produced by neutrophils and other immune cells cleave ECM components including elastin and thrombospondin-1. These cleavage products awaken dormant cancer cells and act as chemotactic agents to recruit immune cells into the tumor microenvironment. Collectively the stromal and immunological components of the tumor microenvironment regulate cancer cell dormancy and outgrowth in the lung. BMDC, bone marrow-derived progenitor cell.

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