Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog

Abstract

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Association of Notch and Hedgehog Pathway Activation With Prognosis in Early-stage Colorectal Cancer

“…Staining intensity was scored as 1+, 2+ and 3+, while the percentage of positive cells was graded as 0 for <5%, 1 for 5-25%, 2 for >26-50%, 3 for >51-75% and 4 for >75%. The product of the intensity and percentage categories (range=0-12) was used as the final score and classified as negative (0-4) and positive (5)(6)(7)(8)(9)(10)(11)(12). Representative staining images of Notch and Hedgehog pathway markers are presented in Figure 2.…”

“…Upon ligand binding, Smo activates the downstream glioma-associated oncogene homologue isoforms (Gli-1,-2,-3) in the cytoplasm, which then translocate to the nucleus, inducing the expression or downregulation of their target genes (mainly regulatory of the cell cycle or proapoptotic genes) (9). Hedgehog, besides other functions, has been found to be involved in tumorigenic development and cancer metastases both in vitro and in vivo (10). It also seems to play an important role in stem cell survival and self-renewal.…”

“…1 (25)(26)(27)(28). Notch can act both as a major oncogene, associated with tumor progression and metastasis, as well as a tumor suppressor (10). It has been also shown that Notch pathway activation contributes to the development and survival of CSCs (29,30).…”

“…The role of Hedgehog and Notch pathways in solid tumors, among which in CRC, has been studied and reviewed quite extensively (32,33). These are master developmental pathways, commonly activated in many tumors in which they not only play a crucial role in tumor initiation, but also in primary and metastatic tumor development and cancer stem cell regulation (10).…”

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

“…Activation of the Wnt/β-catenin signaling pathway decreases phosphorylation of β-catenin in the cytoplasm and increases β-catenin transfer into the nucleus. Consequently, it activates the nuclear complex of β-catenin/T cell factor/lymphoid enhancer factors, and enhances expression level of cell cycle-related molecules such as cyclin-D1 and c-Myc 12,30 . Thus, a discussion of how SOX genes act in the progression of GCs via different signaling pathways, especially the Wnt/β-catenin signaling pathway is presented below.…”