Tumor metastasis: Mechanistic insights and therapeutic interventions

Abstract

Cancer metastasis is responsible for the vast majority of cancer-related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial-mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.

Keywords: cancer; epithelial‐mesenchymal transition; immunotherapy; metastasis; targeted therapy; tumor microenvironment.

FIGURE 1

Overview of the metastatic cascade. Carcinoma cells escaping from the primary tumor migrate and invade through the basement membrane and extracellular matrix, enter the blood or lymphatic vessels, intravasate into the circulation, penetrate the blood or lymphatic vessels (extravasation), and adhere and grow in secondary sites. A variety of stromal cells, immune cells, and other molecular components surrounding the tumor provide signals that enhance the metastatic potential of cancer cells. Platelets and neutrophils can protect tumor cells by providing physical protection against shear stress, secreting mediators (such as transforming growth factor‐beta (TGF‐β)), neutralizing the cytotoxicity of NK cells and favoring immune escape. Abbreviations: BM, basement membrane; CAF, cancer‐associated fibroblast; CTC, circulating tumor cell; ECM, extracellular matrix; EMT, epithelial‐to‐mesenchymal transition; MSC, mesenchymal stem cell; NK cell, natural killer cell; RBC, red blood cell; TAM, tumor‐associated macrophage

FIGURE 2

Cancer cells undergo EMT and invade into circulation. (A) A single transformed epithelial cell remains quiescent for a period of time. (B, C). The transformed cells proliferate and generate a small intraepithelial colony, accompanied by the formation of cancer stem cells. Cancer cells destroy the basement membrane, undergo EMT, and migrate and invade through the basement membrane and extracellular matrix. Normal extracellular matrix undergoes cancer‐associated remodel. Meanwhile, cells and molecular components in tumor microenvironment (TME; CAFs, TAMs, neutrophils, MSCs…) surrounding the primary tumor enhance cancer cell survival, proliferation and metastasis. (D) Cancer cells escaping from primary tumors can invade into the circulation as single CTCs or multicellular CTC clusters. Abbreviations: BM, basement membrane; CAF, cancer‐associated fibroblast; CTC, circulating tumor cell; EC, endothelial cell; ECM, extracellular matrix; EMT, epithelial‐to‐mesenchymal transition; MSC, mesenchymal stem cell; TAM, tumor‐associated macrophage

FIGURE 3

TME involved in the processes of invasion–metastasis cascade. The cellular components in TME can be classified into cancer cells, stromal cells, and immune cells. These cells interact with each other through ligand‐receptor interactions, and the secretion of cytokines, chemokines, exosomes, and extracellular vesicles, forming an evolving microenvironment. Cancer cells that are good at recruiting and establishing a supportive metastatic niche may be able to survive and initiate the process of proliferation and metastasis. The formation of the metastatic niche may occur before the arrival of cancer cells, also known as pre‐metastatic niches. Here, we summarized the role of important cellular components in TME in tumor metastasis