Abstract
Decades of cancer research have unraveled genetic, epigenetic and molecular pathways leading to plausible therapeutic targets; many of which hold great promise in improving clinical outcomes. Metastatic tumors become evident early on and are one of the major causes of cancer-related fatalities worldwide. This review depicts the sequential events of cancer metastasis. Genetic and epigenetic heterogeneity influences local tumor cell invasion, intravasation, survival in circulation, extravasation and colonization to distant sites. Each sequential event is associated with heterogeneous tumor microenvironment, gain of competence, unique population of cancer stem cells (CSCs), circulatory pathway, compatible niche and immune system support. A tight regulation of metastasis-promoting mechanisms and, in parallel, evading inhibitory mechanisms contribute to the severity and site of metastasis. A comprehensive understanding of tumor cell fate as an individual entity, as well as in combination with different promoting factors and associated molecular mechanisms, is anticipated in the coming years. This will enable scientists to depict design strategies for targeted cancer therapies.
Highlights
The past decade has witnessed an immense exploration of the metastatic events in different cancers
A case study, involving identification of genetic markers involved in cancer metastasis, reported Ras, Src and Wnt as the examples of oncogenic signaling pathways found to be consistently dysregulated in a metastatic phenotype [52]
TP53 significantly contributes to metastasis considering that around 50% of human cancers have altered TP53; either mutated or with loss of function
Summary
The past decade has witnessed an immense exploration of the metastatic events in different cancers. It has been reported that approximately 50% of DTCs metastasize to the bone marrow in cancer patients [9] This points out that competence for invasion in a target organ is not necessarily followed by a similar competence for colonization. Reports on the presence of tumors by Greek physicians, between the 5th century and 19th century [13], when the processes of metastasis became evident, showed that cancer metastasizes preferentially to specific organs This preference is favored by compatible surrounding microenvironment. Following that was the hypothesis by Paget which explained that tumor cells were able to colonize a target organ that provided a favorable microenvironment for these cells [14] On the contrary, another group argued that site-specific metastasis was governed solely by the circulatory system [15]. Genetic mutation (one of the contributors to the metastatic potential) may contribute to tumor progression only at one stage of tumor development [25]
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