Targeting crosstalk of signaling pathways in cancer stem cells: a promising approach for development of novel anti-cancer therapeutics

Wnt, Hedgehog (Hh), and Notch signaling pathways are the evolutionarily conserved signaling pathways that regulate the embryonic development and also play crucial role in maintaining stemness properties of cancer stem cells (CSCs) and inducing epithelial-to-mesenchymal transition (EMT), metastasis, and angiogenesis. It has been highly challenging to inhibit the CSCs growth and proliferation as these are capable of evading chemotherapeutic drugs and cause cancer recurrence through multiple signaling pathways. Therefore, novel therapeutic strategies to target the key players involved in the crosstalk of these signaling pathways need to be developed. In this review, we have identified the interacting molecules of Wnt, Hh, and Notch pathways responsible for enhancing the malignant properties of CSCs. Analyzing the functions of these crosstalk molecules will help us to find an approach toward the development of new anti-cancer drugs for inhibition of CSCs growth and progression. Long non-coding RNAs (LncRNAs) play a significant role in various cellular processes, like chromatin remodeling, epigenetic modifications, transcriptional, and post-transcriptional regulations. Here, we have highlighted the research findings suggesting the involvement of LncRNAs in maintenance of the stemness properties of CSCs through modulation of the above-mentioned signaling pathways. We have also discussed about the different therapeutic approaches targeting those key players responsible for mediating the crosstalk between the pathways. Overall, this review article will surely help the cancer biologists to design novel anti-CSCs agents that will open up a new horizon in the field of anti-cancer therapeutics.

Automated summary

Wnt, Hedgehog (Hh), and Notch signaling pathways are crucial for embryonic development and have a significant role in maintaining stemness properties of cancer stem cells (CSCs) and promoting tumor progression. Inhibiting the growth and proliferation of CSCs is challenging, and novel therapeutic strategies targeting the crosstalk of these pathways are needed. This review focuses on the molecules involved in the interaction of Wnt, Hh, and Notch pathways, their role in enhancing CSCs properties, and potential therapeutic approaches. Additionally, the involvement of long non-coding RNAs (LncRNAs) and their modulation of these signaling pathways in CSCs maintenance are discussed. Overall, this review provides valuable insights for the development of new anti-CSCs drugs.