page_title: Invasion (cancer)
section_title: Patterns of invasive growth
hierarchical_section_title: Invasion (cancer) / Patterns of invasive growth
caption_attribution_description: English: Patterns of cancer cell invasion: collective cell and individual cell migration. In collective cell migration, tumor cells exhibit high expression of E-cadherin and integrins. Epithelial-mesenchymal (EMT) and collective-amoeboid (CAT) transitions are a trigger between collective cell invasion and individual cell migration. EMT involves activation of transcription factors, such as TWIST1, Snail, Slug, ZEB1/2, a decrease in E-cadherin expression, and an increase in protease activity. During EMT, tumor cells acquire the mesenchymal phenotype, detach from the tumor mass, and migrate by the mesenchymal mechanism. In contrast, the partial EMT that is specific to the tumor invasive front means that tumor cells retain cell-cell adhesion but already possess migratory ability. This tumor cell phenotype was named the “epithelial-mesenchymal” phenotype. In CAT, which takes place when β1 integrins are down-regulated, tumor cells detach from the tumor mass and move by the amoeboid mechanism. Amoeboid migration involves a decrease in protease and integrin expression and changes in the activity of GTPases – inhibition of Rac1 and activation of RhoA. This movement type occurs in the loose/soft extracellular matrix. In contrast, mesenchymal migration is associated with the opposite phenotype and predominates in the dense/stiff matrix. These two movement types are highly plastic and can convert to each other, depending on the extracellular matrix type and intracellular regulation. Thereby, the mesenchymal-amoeboid (MAT) and amoeboid-mesenchymal (AMT) transitions are suggested
context_page_description: For cancer, invasion is the direct extension and penetration by cancer cells into neighboring tissues. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to more distant locations. Yet, lymphovascular invasion is generally the first step of metastasis.
context_section_description: At present, based on a complex of certain morphological and molecular genetic parameters, two fundamentally different patterns of invasive growth are distinguished: collective (group) cell migration and single cell migration (individual migration: Fig. 1). In this case, the migration type is largely determined by tissue microenvironment features and depends on molecular changes in tumor cells.	
  	
  Determination of the invasion mechanism used by single migrating cells during migration is a complex task. Unfortunately, studies examining this issue at the molecular and morphological levels are few in numbers and mostly were carried out in vitro using specific cell lines.	
  However, now, there is considerable increase in the number of studies that demonstrate increasing interest in research into the molecular genetic features of tumor cells that determine the main differences between the mesenchymal and amoeboid types of cell movement during individual migration, as well as collective migration.	
  Collective migration	
  Collective migration is characterized by the migration of whole groups of cells interconnected by adhesion molecules and other communication junctions (Fig. 1). This is the main feature of this type of invasion, since the underlying cellular mechanisms are the same key processes that largely determine single cell migration.	
  Collective cell migration has been observed in the development and progression of breast and endometrial cancer, prostate cancer, colorectal cancer, largecell lung carcinoma, rhabdomyosarcoma, melanoma, as well as most squamous cell carcinomas.	
  In the case of collective migration, cancer cells, being a part of the tumor mass or detaching from it in the form of multicellular groups, penetrate into the surrounding tissues and form thin short chords, clusters, stripes and wide fields, as well as structures with lumen, that indicate a wide variety of structural elements involved in tumor invasion.	
  As already mentioned, collective migration is characterized by the migration of whole cell groups interconnected by cadherins and intercellular gap junctions. A moving cell group has a “leading edge” or “leading front” that uses integrins and proteases (Fig. 1). Researchers indicate clear differences in the expression of genes and the morphology between the “leader” cells forming the leading edge and the “follower” cells that are located behind them, at the “trailing edge.” The “leaders” in the cell shape often resemble mesenchymal cells and are characterized by a less pronounced ordering and structural organization, while the “followers” tend to form more tightly packed, rosette-like tubular structures with tight intercellular contacts.	
  In the case of collective migration, tumor cells form protrusions (pseudopodia) at the leading edge, use integrins to form focal contacts with the actin cytoskeleton, and perform proteolytic degradation of the extracellular matrix, creating a space for invasion of the tumor tissue and extensively involving the actin-myosin contractile apparatus in the process to ensure successful migration.	
  The differences in the polarity of collectively migrating cell groups are due to the features of expression of surface receptors, such as CXCR4 and CXCR7 chemokine receptors, in the “leader” cells. The growth factors and chemokines produced by stromal cells and a diffusion gradient provide extracellular induction of cell polarization. Involvement of chemokines, such as SDF1 (CXCL12), the fibroblast growth factor (FGF), and the transforming growth factor β (TGF-β), in these processes has been under discussion.	
  Much is known about the involvement of TGF-β in carcinogenesis, with its role being twofold. Taylor et al. have drawn attention to the fact that TGF-β, which acts in the epithelial cells of the mammary gland as a potent tumor suppressor at the early stages of cancer, can affect tumor development via interaction with oncogenic cytokines. Increased expression of TGF-β has been associated with the progression of tumor, which has often been observed, e.g., at the later stages o
caption: Patterns of cancer cell invasion: collective cell and individual cell migration. In collective cell migration, tumor cells exhibit high expression of E-cadherin and integrins. Epithelial-mesenchymal (EMT) and collective-amoeboid (CAT) transitions are a trigger between collective cell invasion and individual cell migration. EMT involves activation of transcription factors, such as TWIST1, Snail, Slug, ZEB1/2, a decrease in E-cadherin expression, and an increase in protease activity. During EMT, tumor cells acquire the mesenchymal phenotype, detach from the tumor mass, and migrate by the mesenchymal mechanism. In contrast, the partial EMT that is specific to the tumor invasive front means that tumor cells retain cell-cell adhesion but already possess migratory ability. This tumor cell phenotype was named the “epithelial-mesenchymal” phenotype. In CAT, which takes place when β1 integrins are down-regulated, tumor cells detach from the tumor mass and move by the amoeboid mechanism. Amoeboid migration involves a decrease in protease and integrin expression and changes in the activity of GTPases – inhibition of Rac1 and activation of RhoA. This movement type occurs in the loose/soft extracellular matrix. In contrast, mesenchymal migration is associated with the opposite phenotype and predominates in the dense/stiff matrix. These two movement types are highly plastic and can convert to each other, depending on the extracellular matrix type and intracellular regulation. Thereby, the mesenchymal-amoeboid (MAT) and amoeboid-mesenchymal (AMT) transitions are suggested.[2]
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