Cancer cells metastasize in several types of cancer via two distinct routes, probably based on mechanical signals

Tumor diseases pose an enormous health threat when they become malignant, as in the process of metastasis. Cancer metastasis has been extensively studied in the past, but attention has been focused primarily on the established intraluminal metastasis route. Research efforts have concentrated on the complex mechanisms behind this process based on biochemical and molecular analyses. Therefore, a comprehensive knowledge of the mechanobiological principles of cancer metastasis and the identification of key molecules and signaling pathways involving mechanical cues are of the utmost importance. Moreover, there are still significant knowledge gaps regarding the two fundamentally different major routes of metastasis, encompassing key mechanosignaling pathways, altered regulation of organ-specific tropism mechanisms, and the impact of the microenvironment, such as mechanical cues. This review examines the stepwise events of cancer metastasis by pointing out the two distinct major routes: intraluminal and extraluminal metastasis. It clarifies the specific processes that underlie the two major metastasis routes with emphasis on mechanobiological characteristics. In addition to classical biochemical features, the review emphasizes the impact of the tumor microenvironment, which is understood to have an immunosuppressive role and seems to mechanically stimulate cancer cells, causing changes in their functional characteristics. The review explores whether the extraluminal metastasis (angiotropism) route of cancer cells could help them to evade mechanical forces that arise during extravasation and intravasation and circumvent the unfavorable environment in hematopoietic or lymphatic vessels, such as forces generated within the vessel lumen caused by the blood flow. The overview explains the advantages and disadvantages of the two major metastasis pathways. It identifies the molecules and signal transduction pathways involved in each pathway. Finally, it is discussed whether these two routes—and possibly a new third interfacial metastasis route—are generally interchangeable and universal in cancer metastasis rather than limited to solely specific cancer types. In addition, the possibility that switching between metastasis pathways serves as an additional regulatory mechanism for cancer metastasis is evaluated. Moreover, the interaction of cancer cells with immune cells, such as neutrophils, is highlighted in both metastasis pathways. Ultimately, it is argued that a more detailed analysis of the relatively new alternative metastasis routes (namely, the extracellular and interfacial metastasis routes) could optimize future treatment options for metastatic cancer.