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Invasion and metastasis are fundamental hallmarks of cancer, representing the ability of the cancer cells to spread from their site of origin to distant tissues and organs. [1]These processes are central to cancer's lethality, accounting for the majority of cancer - related deaths, and marking an important barrier to effective treatment.
These processes enable cancers to establish secondary tumors, contributing to the majority of cancer-related deaths. Understanding and targeting the mechanisms of invasion and metastasis remain pivotal in cancer therapy and research.
Mechanisms of Invasion
editEpithelial-Mesenchymal Transition (EMT)
editEMT is a process where epithelial cells lose their adhesive properties and gain a more mobile, invasive phenotype. [2] This change is regulated by signaling pathways like TGF-B, Wnt, and Notch as well as transcription factors such TWIST, SNAIL, AND ZEB.[3] EMT allows cancer cells to invade surrounding tissues and spread more effectively.
Degradation of the Extracellular Matrix (ECM)
editTo invade nearby tissues, cancer cells cells secrete enzymes such as matrix matalloproteinases (mmps) that degrade the ECM and basement membrane[4] This breakdown creates pathways for cancel cells to migrate and infiltrate new areas.
Tumor Microenvironment
editThe tumor microenvironment, composed of stromal cells, immune cells and singaling molecules, supports invasion by creating good and favorable conditions for tumor cell migration.[5] For example, cancer- associated fibroblasts (CAFS) produce substances that remodel the ECM and promote cancer progression[5]
Local Tissue Invasion
editEpithelial-to-mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and cell-cell adhesion properties and acquire mesenchymal traits, such as enhanced motility and invasiveness. This transformation plays a critical for various physiological processes, such as embryonic development, wound healing, and tissue regeneration. However, in cancer, EMT is often hijacked to promote tumor progression and metastasis. During EMT, epithelial markers like E-cadherin are downregulated, while mesenchymal markers such as N-cadherin and vimentin are upregulated. This change enables cancer cells to detach from the primary tumor, invade surrounding tissues, and ultimately spread to distant locations in the body by entering the bloodstream or lymphatic pathways.[6]
Cancer cells undergo several changes that enable them to invade surrounding tissues. A primary mechanism is the downregulation of E-cadherin which is an epithelial adhesion molecule that helps maintain cell-cell adhesion. Loss of E-cadherin reduces cellular cohesion, allowing cancer cells to detach from the primary tumor. This is a hallmark of epithelial-to-mesenchymal transition (EMT), during which cancer cells acquire mesenchymal traits, such as increased motility and invasiveness.[7][8]
Mechanisms of Metastasis
editIntravastation
editIntravasation is the process where tumor cells enter blood or lymphatic blood vessels, allowing them to travel to distant parts of the body. This step is important in the metastatic journey as it enables tumor cells to leave their original site and circulate through the body. pro- angiogenic factors like VEGF,[9] along with interactions between cancer calls and the vessel walls, make it easier for tumor cells to penetrate into the bloodstream or lymphatic system. By gaining access to these transport networks, cancer cells increase their ability to spread and form new tumors in distant tissues.
Circulating Tumor cells (CTCs)
editWhen cancer cells enter the bloodstream, they are known as circulating tumor cells (CTCs). To protect themselves from being detected and destroyed by the immune system, these cells often group together in clusters or cover themselves with platelets. This protective strategy increases their chances of survival and makes it easier for them to spread to other parts of the body.[10]
Extravasation and Colonization
editExtravasation occurs when circulating tumor cells leave the bloodstream and invade new tissues, guided by molecules like integrins.[11] Integrins help the cells attach and move into their new environment. Once settled, cancer cells form a metastatic niche that helps them grow and establish a new tumor in a new location.
Roles of Biomarkers In Tumor Metastasis
editE-cadherin
editE-cadherin is an epithelial adhesion protein that plays an essential role in maintaining tissue structure by facilitating cell-cell adhesion. Its downregulation is a major feature of EMT transition which is a process that is important for cancer metastasis. The loss of E-cadherin disrupts cellular adhesion, allowing tumor cells to detach from the primary site and invade surrounding tissues. This type of suppression is often mediated by EMT transcription factors such as ZEB1, Snail, and Twist, is then repress E-cadherin gene expression. Furthermore, when E-cadherin is reduced, it facilitates interactions with the extracellular matrix (ECM) which in then enhances the ability of cancer cells to migrate and invade surrounding tissues. By promoting these interactions, E-cadherin is able to support cellular motility and aid tumor cells navigate the tissue structures which drives metastasis [12] [13]. Research emphasizes E-cadherin as a major biomarker in metastatic cancers such as breast and colorectal cancers. Low levels of E-cadherin are often linked to poor clinical outcomes, therapy resistance and aggressive tumor phenotypes[14].
References
edit- ^ Hanahan, Douglas; Weinberg, Robert A (2011-03-04). "Hallmarks of Cancer: The Next Generation". Cell. 144 (5): 646–674. doi:10.1016/j.cell.2011.02.013. PMID 21376230.
- ^ Thiery, Jean Paul; Acloque, Hervé; Huang, Ruby Y.J.; Nieto, M. Angela (November 2009). "Epithelial-Mesenchymal Transitions in Development and Disease". Cell. 139 (5): 871–890. doi:10.1016/j.cell.2009.11.007. PMID 19945376.
- ^ Nieto, M. Angela; Huang, Ruby Yun Ju; Jackson, Rebecca A; Thiery, Jean Paul (June 2016). "EMT: 2016". Cell. 166 (1): 21–45. doi:10.1016/j.cell.2016.06.028. PMID 27368099.
- ^ Egeblad, Mikala; Nakasone, Elizabeth S.; Werb, Zena (June 2010). "Tumors as Organs: Complex Tissues that Interface with the Entire Organism". Developmental Cell. 18 (6): 884–901. doi:10.1016/j.devcel.2010.05.012. PMC 2905377. PMID 20627072.
- ^ a b Kalluri, Raghu (September 2016). "The biology and function of fibroblasts in cancer". Nature Reviews Cancer. 16 (9): 582–598. doi:10.1038/nrc.2016.73. ISSN 1474-175X.
- ^ Celià-Terrassa, Toni; Kang, Yibin (2024-02-07). "How important is EMT for cancer metastasis?". PLOS Biology. 22 (2): e3002487. doi:10.1371/journal.pbio.3002487. ISSN 1545-7885. PMC 10849258. PMID 38324529.
- ^ Liu, Qiu-Luo; Luo, Maochao; Huang, Canhua; Chen, Hai-Ning; Zhou, Zong-Guang (2021-04-29). "Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.657546. ISSN 2234-943X. PMC 8117142. PMID 33996581.
- ^ Sznurkowska, Magdalena K.; Aceto, Nicola (August 2022). "The gate to metastasis: key players in cancer cell intravasation". The FEBS Journal. 289 (15): 4336–4354. doi:10.1111/febs.16046. ISSN 1742-464X. PMC 9546053. PMID 34077633.
- ^ Valastyan, Scott; Weinberg, Robert A. (October 2010). "Tumor Metastasis: Molecular Insights and Evolving Paradigms". Cell. 147 (2): 275–292. doi:10.1016/j.cell.2011.09.024. PMC 3261217. PMID 22000009.
- ^ Aceto, Nicola; Bardia, Aditya; Miyamoto, David T.; Donaldson, Maria C.; Wittner, Ben S.; Spencer, Joel A.; Yu, Min; Pely, Adam; Engstrom, Amanda; Zhu, Huili; Brannigan, Brian W.; Kapur, Ravi; Stott, Shannon L.; Shioda, Toshi; Ramaswamy, Sridhar (August 2014). "Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis". Cell. 158 (5): 1110–1122. doi:10.1016/j.cell.2014.07.013. PMC 4149753. PMID 25171411.
- ^ Massagué, Joan; Obenauf, Anna C. (January 2016). "Metastatic colonization by circulating tumour cells". Nature. 529 (7586): 298–306. Bibcode:2016Natur.529..298M. doi:10.1038/nature17038. ISSN 0028-0836. PMC 5029466. PMID 26791720.
- ^ Cell 100:59
- ^ Evan, GI; Vousden, KH (17 May 2001). "Proliferation, cell cycle and apoptosis in cancer". Nature. 411 (6835): 342–8. Bibcode:2001Natur.411..342E. doi:10.1038/35077213. PMID 11357141. S2CID 4414024.
- ^ Kunst, Claudia; Haderer, Marika; Heckel, Sebastian; Schlosser, Sophie; Müller, Martina (December 2016). "The p53 family in hepatocellular carcinoma". Translational Cancer Research. 5 (6): 632–638. doi:10.21037/tcr.2016.11.79. ISSN 2219-6803.