Cancer Invasion: Patterns and Mechanisms

Abstract

Cancer invasion and the ability of malignant tumor cells for directed migration and metastasis have remained a focus of research for many years. Numerous studies have confirmed the existence of two main patterns of cancer cell invasion: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid- mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumoral morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.

Keywords: cancer; cell migration; collective cell migration; individual cell migration; invasion.

Fig. 1

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 [1, 13, 22, 47, 68, 73, 74]

Fig. 2

Intratumoral morphological heterogeneity in invasive breast carcinoma. Diversity of invasive growth of breast cancer is shown, which can be classified into five main morphological structures: alveolar (Alv), trabecular (Trab), tubular (Tub), solid (Solid) structures, and discrete groups of tumor cells (Discr). Hematoxylin and eosin staining. Magnification of 200x