Introduction

Metastasis is the process by which cancer cells spread from the primary tumor site to distant organs or tissues, forming secondary tumors. It is responsible for approximately 90% of cancer-related deaths and remains one of the greatest challenges in cancer treatment. Understanding the complex mechanisms underlying metastasis is crucial for the development of novel therapeutic strategies aimed at preventing and treating cancer dissemination.

The metastatic cascade

Metastasis is a multi-step process that involves several distinct stages, collectively known as the metastatic cascade:

1. Local invasion: Cancer cells at the primary tumor site undergo changes in gene expression and behavior, acquiring invasive properties. This epithelial-to-mesenchymal transition (EMT) allows cancer cells to break away from the primary tumor, degrade the extracellular matrix, and invade the surrounding tissue.
2. Intravasation: After invading the surrounding tissue, cancer cells enter the bloodstream or lymphatic vessels (intravasation) and become circulating tumor cells (CTCs).
3. Survival in circulation: To successfully metastasize, CTCs must evade immune detection and withstand the physical stress of circulation. Only a small fraction of CTCs survive this stage.
4. Extravasation: CTCs exit the bloodstream or lymphatic vessels (extravasation) and invade the tissue of a distant organ.
5. Colonization and secondary tumor formation: After extravasation, cancer cells must adapt to the new tissue environment, proliferate, and establish a secondary tumor. This stage, known as colonization, is facilitated by the reciprocal interaction between cancer cells and the surrounding stromal cells, which constitute the tumor microenvironment.

Factors influencing metastasis

1. Tumor cell properties: Genetic and epigenetic alterations in cancer cells can affect their metastatic potential. For example, mutations in oncogenes and tumor suppressor genes can drive the acquisition of invasive properties and resistance to apoptosis.
2. Tumor microenvironment: The tumor microenvironment, consisting of various cell types (e.g., fibroblasts, immune cells) and extracellular matrix components, can promote or suppress metastasis. Inflammatory and immune cells can either eliminate cancer cells or support their survival and spread, depending on the balance of pro- and anti-tumor signals.
3. Organotropism: Cancer cells have a preference for specific target organs, a phenomenon known as organotropism. This is influenced by factors such as chemokines, adhesion molecules, and the tumor cell’s compatibility with the target organ’s microenvironment.

Therapeutic strategies targeting metastasis

Preventing and treating metastasis is an essential goal in cancer therapy. Several strategies have been investigated to target different stages of the metastatic cascade:

1. Inhibiting EMT and invasion: Therapeutic agents that target molecular pathways involved in EMT and local invasions, such as TGF-β, Wnt, and Notch signaling, are under investigation.
2. Targeting circulating tumor cells: Strategies to eliminate CTCs include immunotherapies that harness the immune system to recognize and destroy CTCs or drugs that specifically target CTCs based on their unique molecular markers.
3. Blocking extravasation and colonization: Therapies targeting adhesion molecules and signaling pathways that facilitate extravasation and colonization are being explored. For example, inhibitors of CXCR4, a chemokine receptor involved in organotropism, have shown promise in preclinical studies.
4. Targeting the tumor microenvironment: Strategies aimed at modulating the tumor microenvironment to suppress metastasis include anti-angiogenic agents, immunotherapies, and stromal cell-targeting therapies