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Review
. 2015;9(5):345-56.
doi: 10.1080/19336918.2015.1059563. Epub 2015 Aug 27.

Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both?

Affiliations
Review

Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both?

Ana Sofia Azevedo et al. Cell Adh Migr. 2015.

Abstract

Metastasis is the end product of a multistep process where cancer cells disseminate and home themselves in distant organs. Tumor cell extravasation is a rare, inefficient and transient event in nature and makes its studies very difficult. Noteworthy, little is known about how cancer cells arrest, adhere and pass through the endothelium of capillaries. Moreover, the key events driving metastatic growth in specific organs are not well understood. Thus, although metastasis is the leading cause of cancer-related death, how cancer cells acquire their abilities to colonize distant organs and why they do so in specific locations remain central questions in the understanding of this deadly disease. In this review, we would like to confront 2 concepts explaining the efficiency and location of metastatic secondary tumors. While the "seed and soil" hypothesis states that metastasis occurs at sites where the local microenvironment is favorable, the "mechanical" concept argues that metastatic seeding occurs at sites of optimal flow patterns. In addition, recent evidence suggests that the primary event driving tumor cell arrest before extravasation is mostly controlled by blood circulation patterns as well as mechanical cues during the process of extravasation. In conclusion, the organ tropism displayed by cancer cells during metastatic colonization is a multi-step process, which is regulated by the delivery and survival of circulating tumor cells (CTCs) through blood circulation, the ability of these CTCs to adhere and cross the physical barrier imposed by the endothelium and finally by the suitability of the soil to favor growth of secondary tumors.

Keywords: extravasation, metastasis, microenvironment, biomechanics, blood flow, circulating tumor cell.

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Figures

Figure 1.
Figure 1.
Efficiency of the metastasis cascade. The metastasis cascade starts with the shedding of tumor cells within the circulation. Travelling CTCs will eventually seed distant organ and form clinically detectable macrometastases. The efficiency of this multi-step process is mostly driven by mechanical cues such as hemodynamic patterns, which will determine where CTCs will arrest and extravasate out of the vasculature. This is the first event controlling the efficiency of the metastatic process. It is then followed by indoctrination of the chosen stroma that, if fertile enough, will provide solid ground for successful metastatic growth.
Figure 2.
Figure 2.
Arrest of CTCs by physical constraints. The initial delivery and arrest of CTCs is primarily regulated by physical parameters imposed by the architecture and diameter of small capillaries irrigating important organs such as the brain, the liver and the lungs, all known as preferred organs for metastatic seeding. Because CTCs are bigger than CBCs and WBCs, capillary-type blood circulation will trap them by size restriction, allowing successful extravasation and growth of secondary foci. This method of arrest of CTCs arrest questions the importance of active adhesion between metastatic cells and the endothelium.
None

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