Invasion (cancer)

Invasion is the process by which cancer cells directly extend and penetrate into neighboring tissues in cancer. 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. The two are nonetheless closely related, and lymphovascular invasion is generally the first step of metastasis. The two main patterns of cancer cell invasion by cell migration are collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Either pattern of cell migration exhibits distinct morphological features and is governed by specific biochemical and molecular genetic mechanisms. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, can be observed in various patterns of cancer cell invasion. This article describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal and related transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. Morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures.

Invasive growth and metastasis The results of numerous experimental and clinical studies of malignant neoplasms have indicated that invasive growth and metastasis are the main manifestations of tumor progression, which constitute two closely related processes. A malignant tumor is defined by its capacity to initiate a biological phenomenon known as the metastatic cascade, a complex multi-stage process in which cell invasion precedes further cancer progression and the formation of metastases in distant organs and tissues. Massive metastatic lesions lead to the development of organ failure. The range between the "end" points of a complex invasive metastatic process–an invasion of the primary tumor into surrounding tissues and the formation of metastatic foci–comprises several stages, the passage of which is strictly necessary for the successful development and subsequent progression of tumor growth: intravasation, survival and presence in the systemic circulation, extravasation with subsequent colonization of organs by tumor cells, and the formation of clinically detectable metastases. Tumor growth is accompanied by increasing pressure on surrounding extracellular matrix structures, whereas the tissue microenvironment works to retain its functional-anatomic integrity by increasing pressure on the tumor cells. The factors limiting the growth of malignant neoplasms include the basement membrane and various components of the surrounding stroma, increased interstitial pressure, limited oxygen supply to tumor cells and the production of reactive oxygen species, and persistent contact with immune system cells. Due to intratumoral heterogeneity, some tumor cells may undergo regression and death, while others, resilient against opposing microenvironmental factors, acquire an aggressive phenotype and the capacity to metastasize. Invasive tumor growth is enabled by the detachment of malignant cells from the tumor mass due to a reduction in or complete loss of intercellular adhesion molecules. This allows the cells to gain anomalously high motility enabling penetration through the stiff structural elements of the surrounding stroma. The process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells, is referred to as an epithelial-mesenchymal transition (EMT). EMTs are a normal feature of diverse biological processes such as embryogenesis and wound healing. However, in the context of metastasis, they facilitate the invasion of tumor cells into other areas of the body.

Physiological prototypes of invasive growth Tumor cells have the ability to replicate the mechanisms and migration patterns typically seen in normal, non-tumor cells during various physiological processes. Like normal cells, tumor cells can activate these mechanisms to alter their shape, create favorable conditions for movement, and reshape nearby tissues to form pathways for migration. However, tumor cells, in contrast to normal cells, do not have physiological "stop signals" to terminate these processes. This leads to the establishment of the migration mechanisms and promotes the progression and spread of the tumor. Malignant cells were found to use built-in genetic programs to implement the processes that determine invasive growth and metastasis. For example, the movement of individual cells observed during embryonic development and inflammation (e.g., leukocyte migration) is similar to the dissemination of cancer cells during tumor progression and metastasis. Along with single cell migration, collective cell migration can occur when groups of firmly interconnected tumor cells migrate together. This type of migration indicates tissue rearrangement, underlies the processes of embryonic morphogenesis, and is also an essential component of the healing of wound surfaces. In this way malignant tumor cells use the mechanisms of both collective and single cell migration as physiological prototypes in the process of invasive growth and metastasis.

Patterns of invasive growth Two distinct patterns of invasive growth are distinguished based on specific morphological and molecular genetic parameters: single-cell migration and collective cell migration. The migration type is predominantly influenced by characteristics of the tissue microenvironment, and is dependent on molecular changes within the tumor cells.

Determination of the invasion mechanism used by single migrating cells during migration is a complex task. Before 2015, studies examining this at the molecular and morphological levels were few in numbers and mostly were carried out in vitro using specific cell lines. However, there has been a subsequent increase in the number of studies that demonstrate interest in 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.

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