Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives

Abstract

Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. Despite its significance, the mechanisms governing metastasis are not fully elucidated. Contemporary findings in the domain of cancer biology have shed light on the molecular aspects of this intricate process. Tumor cells undergoing invasion engage with other cellular entities and proteins en route to their destination. Insights into these engagements have enhanced our comprehension of the principles directing the movement and adaptability of metastatic cells. The tumor microenvironment plays a pivotal role in facilitating the invasion and proliferation of cancer cells by enabling tumor cells to navigate through stromal barriers. Such attributes are influenced by genetic and epigenetic changes occurring in the tumor cells and their surrounding milieu. A profound understanding of the metastatic process's biological mechanisms is indispensable for devising efficacious therapeutic strategies. This review delves into recent developments concerning metastasis-associated genes, important signaling pathways, tumor microenvironment, metabolic processes, peripheral immunity, and mechanical forces and cancer metastasis. In addition, we combine recent advances with a particular emphasis on the prospect of developing effective interventions including the most popular cancer immunotherapies and nanotechnology to combat metastasis. We have also identified the limitations of current research on tumor metastasis, encompassing drug resistance, restricted animal models, inadequate biomarkers and early detection methods, as well as heterogeneity among others. It is anticipated that this comprehensive review will significantly contribute to the advancement of cancer metastasis research.

Fig. 1

The significant history and progress of cancer metastasis. Timeline of pivotal discoveries in cancer metastasis research from 1820 to 2020, showcasing milestones such as the “Seed and soil” hypothesis, micro-RNA’s role, organ specificity, genetic and epigenetic influences, and the impact of cellular interactions and the gut microbiome on metastatic progression. Created with BioRender.com

Fig. 2

The chart categorizes a range of cancers, including melanoma, thyroid adenocarcinoma, and others, and identifies the most frequently mutated driver genes associated with each. These mutations are crucial for the development and progression of the respective cancers and may serve as potential therapeutic targets. It underscores the importance of understanding these mutations for the development of personalized medicine and targeted cancer therapies. Created with Figuredraw.com

Fig. 3

Classic signaling pathways related to tumor metastasis. Among them, MAPK, PI3K-AKT, TGF-β, JAK-STAT are phosphorylation-based signaling pathways that are cascaded and amplified by extracellular activating factors into the cell, ultimately entering downstream nuclear transcription regulation. Wnt and NF-κB signaling pathway are signal forms based on phosphorylation and protein ubiquitination degradation, which are also widely expressed. Notch is a protein shear-dependent signaling pattern. A significant feature that distinguishes the STING pathway from several other immune signaling mechanisms is that its activation is triggered by DNA, thus lacking any pathogen specificity. Created with BioRender.com

Fig. 4

Diagram of the tumor microenvironment showing representative cell types, signaling factors, and various cytokines, as well as their mechanisms of action. At the tumor site, immune cells typically obtain tumor-related immunosuppressive phenotypes, except for cytotoxic CD8⁺lymphocytes (CTLs) that kill cancer cells. Myeloid-Derived Suppressor Cells (MDSCs) suppress immunity through various mechanisms. MDSCs can also induce T regulatory (Treg) cells, inhibit natural killer (NK) cells, and promote Tumor-Associated Macrophages (TAMs) with type 2 phenotype. Fibroblasts become Cancer-Associated Fibroblasts (CAFs), promoting extracellular matrix (ECM) remodeling. The extracellular vesicles released by various cells contain proteins, mRNA, and microRNAs that affect the microenvironment. Fibrotic cytokines recruit immune cells. Neutrophil Extracellular Traps (NETs) released by neutrophils after being stimulated can capture cancer cells. TAMs, TANs, and CAFs release angiogenic cytokines and Matrix Metalloproteinases (MMPs), promoting angiogenesis and ECM degradation, and promoting potential metastasis. In addition, the effects of cytokines are represented by red (tumor-promoting) and blue (anti-tumor) rectangles. Some cytokines, such as transforming growth factor- β (TGF-β), can have a dual effect, serving as both an anti-tumor factor and a tumor promoting factor depending on the situation. Created with BioRender.com

Fig. 5

Tumor metabolism can be divided into three levels: 1. Involving the intake of nutrients such as glucose, amino acids, and nitrogen. Immune cells mainly consume glucose, while tumor cells mainly consume amino acids and fatty acids. Glutamine serves as a nitrogen donor for purines, pyrimidines, and non essential amino acids, as well as a carbon donor. Cancer cells can obtain amino acids from extracellular proteins through microcytosis. 2. Changes in metabolic processes: Tumor cells utilize TCA cycle intermediates for NADPH biosynthesis and production. At the same time, the increase in nitrogen demand leads to an upregulation of the transcription factor c-Myc in proliferating cells, leading to increased uptake of glutamine by cells. 3. The role of metabolites: Tumor metabolites can drive abnormal gene expression and interact with the surrounding microenvironment. The high utilization of extracellular glucose and glutamine by cancer cells leads to the accumulation of extracellular lactate, which has been shown to affect several cell types in the tumor microenvironment. The increase in lactate levels also promotes the emergence of favorable microenvironments for tumor cells. Created with BioRender.com

Fig. 6

Lipid metabolism and its role in cancer metastasis. This figure illustrates the critical role of lipid metabolism in the progression and dissemination of cancer cells. Highlighted are the key functions of lipids beyond energy storage, including their involvement in membrane formation, energy production, and modulation of signaling pathways that influence cell migration, invasion, and survival. The figure also encapsulates significant research findings, such as the correlation between fatty acid metabolism and immunosuppression in male breast cancer, the prognostic value of fatty acid synthase (FASN) expression in cervical cancer, and the impact of metabolic reprogramming on lymph node metastasis. Additionally, it underscores the influence of lipid metabolism on immune cell function and the tumor-promoting activities of metastasis-associated macrophages and cancer-associated fibroblasts. Created with BioRender.com

Fig. 7

Amino acid metabolism in cancer metastasis. Metabolic rewiring: Illustrates the critical role of amino acid metabolism reprogramming in supporting tumor growth, immune evasion, and metastatic spread. Arginine metabolism: Highlights the influence of VIPR1 activation and FOXO3a-regulated metabolic plasticity on HCC and ESCC progression, with a focus on ASS1 and ASL enzymes. Glutamine and Serine metabolism: Shows the impact of GOT2 downregulation and ZEB1-mediated SSP reprogramming on HCC, and the role of ANGPTL4 in NSCLC metastasis. Asparagine metabolism: Depicts the effects of targeting glutamine metabolism in PDAC and the significance of ASNS in various cancers, emphasizing its role in tumor cell proliferation and metastasis. Created with BioRender.com

Fig. 8

There are many options for cancer treatment. The type and stage of cancer you suffer from will determine the type of treatment you receive. Some cancer patients only receive one type of treatment. However, most patients use combination and personalized treatment, such as surgery combined with chemotherapy and/or radiation therapy. The emergence of targeted therapy and immunotherapy, including immune checkpoint inhibitors, cell therapy, adoptive cell transfer (ACT) based immunotherapy, tumor vaccines, and nanotechnology, has completely changed the treatment of cancer. At the same time, some emerging therapies, such as oncolytic virus therapy and antibody drug coupling therapy, are working towards cancer treatment. Created with BioRender.com