Journal of Carcinogenesis & Mutagenesis

Metastasis as a Key Step in Cancer Development

Chan Liu^* Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, D, Korea
^*Correspondence: Chan Liu, Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, D, Korea, Email:

Received: 29-Aug-2025, Manuscript No. JCM-25-30674; Editor assigned: 01-Sep-2025, Pre QC No. JCM-25-30674 (PQ); Reviewed: 15-Sep-2025, QC No. JCM-25-30674; Revised: 22-Sep-2025, Manuscript No. JCM-25-30674 (R); Published: 29-Sep-2025, DOI: 10.35248/2157-2518.25.16.005

Description

Metastasis is the process by which cancer cells spread from a primary tumor to distant organs, establishing secondary tumors. It represents a critical step in cancer development and is responsible for the majority of cancer-related deaths. Metastasis is a complex, multistep process involving detachment from the primary tumor, invasion into surrounding tissues, intravasation into the circulatory or lymphatic system, survival in transit, extravasation into distant tissues, and colonization to form secondary tumors [1]. Understanding the mechanisms of metastasis is essential for developing diagnostic, prognostic, and therapeutic strategies in cancer management.

The first step in metastasis is the detachment of tumor cells from the primary site. Alterations in cell adhesion molecules such as E-cadherin reduce intercellular cohesion and facilitate the release of individual cancer cells [2]. These changes are often driven by genetic mutations and epigenetic modifications that disrupt normal cellular architecture. Additionally, Epithelial-to-Mesenchymal Transition (EMT) plays a central role in this process. During EMT, epithelial cancer cells acquire mesenchymal characteristics, including enhanced motility, invasiveness, and resistance to apoptosis. This phenotypic change allows cells to penetrate surrounding tissues and invade the extracellular matrix [3].

Following invasion, tumor cells enter the circulation through a process called intravasation. Interaction with stromal cells, immune cells, and endothelial cells facilitates this entry. Tumor cells face significant challenges in circulation, including shear stress, immune surveillance, and anoikis, a form of apoptosis induced by loss of adhesion [4]. Only a small fraction of circulating tumor cells survives these conditions, highlighting the selective nature of metastasis. Survival is often aided by platelet coating and secretion of survival factors, which shield tumor cells and enhance their ability to reach distant sites [5].

Extravasation, the exit of tumor cells from the circulation, is guided by molecular interactions between tumor cells and endothelial cells in the target tissue. Chemokine gradients, adhesion molecules, and integrins direct tumor cells to specific organs, explaining patterns of organ-specific metastasis. Once in the secondary site, tumor cells must adapt to the local microenvironment, which may differ significantly from the primary tumor [6]. This adaptation requires changes in metabolism, evasion of immune surveillance, and interaction with stromal and immune cells to support survival and growth.

Genetic and epigenetic alterations underlie the ability of tumor cells to metastasize. Mutations in oncogenes and tumor suppressor genes can promote motility, invasiveness, and resistance to apoptosis [7]. Chromosomal instability and copy number variations create heterogeneous populations within tumors, allowing selection of subclones with high metastatic potential. Epigenetic changes, including DNA methylation, histone modifications, and dysregulated non-coding RNAs, regulate gene expression patterns essential for EMT, invasion, and colonization. Together, these alterations enable cancer cells to complete the multistep metastatic cascade [8].

The tumor microenvironment also plays a critical role in metastasis. Cancer-associated fibroblasts remodel the extracellular matrix to facilitate invasion, while immune cells secrete cytokines and growth factors that promote tumor progression [9]. Hypoxic regions in tumors stabilize transcription factors such as HIF-1α, which induce angiogenesis and support survival under stress. These microenvironmental interactions create conditions favorable for metastatic dissemination and colonization of distant tissues.

Metastasis is clinically significant because it is the primary cause of cancer morbidity and mortality. Early detection of metastatic potential is important for prognosis and treatment planning. Advances in molecular profiling, liquid biopsy, and imaging techniques allow identification of metastatic markers and circulating tumor cells, enabling timely intervention [10]. Therapeutic strategies targeting metastatic pathways, including inhibitors of EMT, angiogenesis, and adhesion molecules, are under investigation to reduce metastatic spread and improve patient outcomes.

Conclusion

In metastasis is a central step in cancer development, involving a series of coordinated events that allow tumor cells to spread and colonize distant organs. Genetic and epigenetic alterations, phenotypic plasticity, and interactions with the microenvironment collectively enable this process. Understanding the molecular and cellular mechanisms of metastasis provides critical insight into cancer progression and offers opportunities for developing early detection methods, targeted therapies, and strategies to reduce metastasis-related mortality.

References

1. Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell. 2023;186(8):1564-79.

   [Crossref] [Google Scholar] [PubMed]

2. Udagawa T. Tumor dormancy of primary and secondary cancers. APMIS. 2008;116(7�8):615-28.

   [Crossref] [Google Scholar] [PubMed]

3. Swartz MA. The physiology of the lymphatic system. Advanced drug delivery reviews. 2001;50(1-2):3-20.

   [Google Scholar]

4. Nguyen-Nielsen M, Borre M. Diagnostic and therapeutic strategies for prostate cancer. Semin Nucl Med. 2016;(46) 6, (484-490).

   [Crossref] [Google Scholar] [PubMed]

5. Roche J. The epithelial-to-mesenchymal transition in cancer. Cancers. 2018;10(2):52.

   [Google Scholar]

6. Weber M, Hauschild R, Schwarz J, Moussion C, De Vries I, Legler DF, et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science. 2013;339(6117):328-32.

   [Crossref] [Google Scholar] [PubMed]

7. Swann JB, Smyth MJ. Immune surveillance of tumors. The Journal of clinical investigation. 2007; 117(5):1137-46.

   [Crossref] [Google Scholar] [PubMed]

8. Stehr H, Jang SH, Duarte JM, Wierling C, Lehrach H, Lappe M, et al. The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors. Mol Cancer. 2011;10(1):54.

   [Crossref] [Google Scholar] [PubMed]

9. Lacy P. Secretion of cytokines and chemokines by innate immune cells. Front Immunol. 2015;22;(6)190.

   [Crossref] [Google Scholar] [PubMed]

10. Folkman J. Angiogenesis. Annu. Rev. Med. 2006;57(1):1-8.

    [Google Scholar]