The Role of the ECM in Lung Cancer Dormancy and Outgrowth.

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.