Mechanisms of Tumor Metastasis and Treatment Approaches

The review article "Multi-stage Mechanisms of Tumor Metastasis and Therapeutic Strategies" provides a detailed review of cancer metastasis, a leading cause of cancer-related mortality. Metastasis refers to the process by which tumor cells spread from their primary site to distant organs, significantly contributing to the disease's lethality. The metastasis cascade involves several stages: invasion, intravasation, circulation, extravasation, and colonization. Circulating tumor cells (CTCs) leave the primary tumor, survive in the bloodstream, and eventually establish secondary tumors in distant organs.

A crucial factor in organ-specific metastasis is the formation of pre-metastatic niches (PMNs). These PMNs prepare distant organs for colonizing CTCs, making them more receptive to tumor growth. Primary tumors release extracellular vesicles that carry factors promoting PMN development, including the modulation of immune responses and enhancing cancer cell survival. The PMN is a dynamic environment composed of immune cells, stromal cells, and the extracellular matrix (ECM), with intricate interactions that facilitate tumor progression.

One of the key challenges in treating metastasis is tumor dormancy. Even after successful cancer treatments, residual cancer cells can remain dormant for years, escaping immune surveillance and avoiding detection. These dormant CTCs often undergo genetic and functional alterations, allowing them to resist treatments and eventually reawaken to form new metastatic tumors. This dormancy poses a significant hurdle in cancer therapy, as metastatic disease can recur long after the primary tumor has been controlled.

Epithelial-mesenchymal transition (EMT) is a critical process in metastasis, enabling tumor cells to acquire the migratory and invasive capabilities necessary for spreading. However, only a tiny fraction of CTCs undergoing EMT survive through the bloodstream and successfully colonize distant organs. These surviving cells enhance their metastatic potential through interactions with immune and stromal cells, which help them evade destruction by the immune system.

Immune evasion plays a fundamental role in tumor progression, particularly within the PMN. Tumor cells can manipulate their microenvironment to create an immunosuppressive niche, reprogramming immune cells like macrophages and T cells into pro-tumorigenic states. The microenvironment's hypoxic and metabolically altered conditions further contribute to immune cell exhaustion, allowing tumor cells to thrive unchecked.

The authors emphasize the importance of early intervention to combat metastasis. Rather than passively waiting for macrometastasis, it advocates for treatments that disrupt the metastatic process at its earlier stages. Therapeutic strategies targeting the PMN, enhancing immune responses, and preventing the reawakening of dormant cells show significant promise. The article also looks at potential therapies to prevent circulating tumor cells (CTCs) from adapting to new environments and disrupting epithelial-mesenchymal transition (EMT) processes.

A significant challenge in treating metastatic cancer is the development of drug resistance. Cancer cells often acquire resistance through genetic mutations or epigenetic changes, complicating the efficacy of current treatments. The article outlines various mechanisms of drug resistance observed during different stages of metastasis. It highlights the need for novel therapeutic strategies to overcome resistance, including targeting metabolic pathways and leveraging immune-based therapies to restore effective anti-tumor responses.

Liu, Z., Chen, J., Ren, Y. et al. Multi-stage mechanisms of tumor metastasis and therapeutic strategies. Sig Transduct Target Ther 9, 270 (2024). https://doi.org/10.1038/s41392-024-01955-5