Roles for growth factors and mutations in metastatic dissemination

Abstract

Cancer is initiated largely by specific cohorts of genetic aberrations, which are generated by mutagens and often mimic active growth factor receptors, or downstream effectors. Once initiated cells outgrow and attract blood vessels, a multi-step process, called metastasis, disseminates cancer cells primarily through vascular routes. The major steps of the metastatic cascade comprise intravasation into blood vessels, circulation as single or collectives of cells, and eventual colonization of distant organs. Herein, we consider metastasis as a multi-step process that seized principles and molecular players employed by physiological processes, such as tissue regeneration and migration of neural crest progenitors. Our discussion contrasts the irreversible nature of mutagenesis, which establishes primary tumors, and the reversible epigenetic processes (e.g. epithelial–mesenchymal transition) underlying the establishment of micro-metastases and secondary tumors. Interestingly, analyses of sequencing data from untreated metastases inferred depletion of putative driver mutations among metastases, in line with the pivotal role played by growth factors and epigenetic processes in metastasis. Conceivably, driver mutations may not confer the same advantage in the microenvironment of the primary tumor and of the colonization site, hence phenotypic plasticity rather than rigid cellular states hardwired by mutations becomes advantageous during metastasis. We review the latest reported examples of growth factors harnessed by the metastatic cascade, with the goal of identifying opportunities for anti-metastasis interventions. In summary, because the overwhelming majority of cancer-associated deaths are caused by metastatic disease, understanding the complexity of metastasis, especially the roles played by growth factors, is vital for preventing, diagnosing and treating metastasis.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells

“…Both tumor autonomous mechanisms and adaptive survival signaling may be related to melanoma progression and drug resistance. Once the processes of melanoma progression have been initiated, tumor cells tend to detach from their natural binding partners, namely keratinocytes, to interact with host cells such as fibroblasts and endothelial cells [2,264], inducing the secretion of the hepatocyte growth factor (HGF), endothelial growth factor (EGF), neuregulin (NRG), and IGF-1R [265][266][267]. Secretion of these tumor-derived growth factors often occurs in response to treatment with BRAF inhibitors, a common mechanism by which melanoma cells confer resistance to BRAF inhibitors [268,269].…”

Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer

“…In addition, the urokinase-type plasminogen activation system also disrupts the peritoneal barrier by activating pro-MMPs and degrading ECMs [19]. Subsequently, tumor cells along with stromal cells generate various growth factors represented by epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 (IGF-1) via autocrine and paracrine pathways to stimulate the continuous proliferation of cancer cells [20]. Under a hypoxic environment, the expression of hypoxia-inducible factor 1α (HIF-1α) is significantly elevated in PM, further activating the transcription of angiogenesis-related genes including the vascular endothelial growth factor (VEGF) family [21,22], promoting the development of new microvessels and lymphatic vessels to obtain nutrients and oxygen, and finally leading to the formation of lymphatic metastasis and cancerous ascites (Figure 1).…”

fMetastatic potential in clonal melanoma cells is driven by a rare, early-invading subpopulation

“…At the single cell level, the molecular differences between the cells primed for invasion and the bulk of the primary tumor could take several forms. Classically, genetic differences (i.e., mutations) had been thought to be the driver behind the transitions(Nataraj et al, 2021; Nguyen et al, 2022); however, in recent years, it has become clear that non-genetic changes in regulatory programs and pathways can also drive the switch to the invasive phenotype(Arozarena and Wellbrock, 2019; Quinn et al, 2021; Rambow et al, 2019). In melanoma, these changes have been referred to as phenotype switching, which is largely driven by changes in Wnt signaling and the microenvironment(Kim et al, 2017; Webster et al, 2020; Widmer et al, 2013).…”