Remodeling the ECM: Implications for Metastasis and Tumor Dormancy

Abstract

While most primary tumors can be effectively treated, therapeutics fail to efficiently eliminate metastases. Metastases arise from cancer cells that leave the primary tumor and seed distant sites. Recent studies have shown that cancer cells disseminate early during tumor progression and can remain dormant for years before they resume growth. In these metastatic organs, cancer cells reside in microenvironments where they interact with other cells, but also with the extracellular matrix (ECM). The ECM was long considered to be an inert, non-cellular component of tissues, providing their architecture. However, in recent years, a growing body of evidence has shown that the ECM is a key driver of cancer progression, and it can exert effects on tumor cells, regulating their metastatic fate. ECM remodeling and degradation is required for the early steps of the metastatic cascade: invasion, tumor intravasation, and extravasation. Similarly, ECM molecules have been shown to be important for metastatic outgrowth. However, the role of ECM molecules on tumor dormancy and their contribution to the dormancy-supportive niches is not well understood. In this perspective article, we will summarize the current knowledge of ECM and its role in tumor metastasis and dormancy. We will discuss how a better understanding of the individual components of the ECM niche and their roles mediating the dormant state of disseminated tumor cells (DTCs) will advance the development of new therapies to target dormant cells and prevent metastasis outgrowth.

Keywords: ECM; cancer dormancy; metastasis.

Figure 1

The seed at the center of Paget’s theory. Cancer cells (represented in blue) disseminate to a distant site. (1) The seed (cancer cells) will first sense and attach to the “Soil ECM” (represented in yellow). (2) The seed will also secrete the “Seed ECM” (blue). (3) In the context of dormancy, this “seed ECM” will sustain the dormant state of the seed itself and influence the stromal cells to adapt their ECM production (red). (4) This ECM produced by stromal cell (red) in response to the dormant cells will then be able to signal back to the stroma itself and to the seed.

Figure 2

ECM effects on cancer cells during tumor dormancy. Cancer cells (represented in blue) leave the primary tumor and colonize a secondary distant site. In this new site, they encounter new environments that will vary in ECM composition and organization. The repertoire of receptors in these cells may determine their fate, dormancy, or proliferation. Cancer treatments and aging are factors that can influence the ECM architecture of a tissue and influence the escape from dormancy. Collagens are represented in pink, proteoglycans in grey, and ECM receptors in purple and yellow.