Cancer Metastasis: Dynamic Hetero-cellular Communications Between Cancer Cells and Host Tissues

Abstract

Metastasis is the most devastating aspect of cancer. Originally, tumor cells arise from a single clone, and then they undergo additional mutations and acquire invasive and metastatic features. These acquired mutations are essential to enhance motility and plasticity of tumor cells and modulate their metastatic microenvironment, enabling their colonization to secondary sites. The complexity of metastasis involves a dynamic interplay between tumor cells, and their microenvironment, which results in the development of distant secondary tumor colonies. At the primary tumor microenvironment (TME), cancer cells interact with stromal cells, fibroblasts, and immune cells (macrophages, dendritic cells, neutrophils, mast cells, and lymphocytes), and corrupt them to promote malignant cell survival, growth, and angiogenesis. A number of cancer cells from the primary tumor acquire special features that allow them to leave the primary tumor site, enter the bloodstream (intravasate), exit the bloodstream (extravasate), and form distant colonies and secondary tumor sites. Survival of these circulating cancer cells (CTCs) in the blood is intricately subject to their interaction with immune cells in the bloodstream. All of these metastatic processes rely on transient and prolonged cell-cell communication modalities through surface adhesion molecules, gap junctions, and extracellular vesicles (EVs). In recent years, interest in EVs has witnessed an extraordinary expansion, and a special subtype of EVs, exosomes, is regarded as a novel mode of targeted intercellular communication serving physiological and pathological (malignant) functions. This chapter aims to recapitulate the journey of malignant cells leaving the primary tumor site, travelling through the blood and lymphatic vessels and invading distant sites. Following an overview of the metastatic process, this chapter tackles the primary tumor niche, the immune components of the TME, the interactions between CTCs and immune cells, angiogenesis and intravasation/ extravasation of metastasizing cancer cells, as well mechanisms of communication between malignant and normal cells. While some classical papers are cited to reflect long-established concepts, the below material includes a state-of-the-art review of the most recent literature on the subject.