Notch receptor/ligand diversity: contribution to colorectal cancer stem cell heterogeneity

Abstract

Cancer cell heterogeneity is a key contributor to therapeutic failure and post-treatment recurrence. Targeting cell subpopulations responsible for chemoresistance and recurrence seems to be an attractive approach to improve treatment outcome in cancer patients. However, this remains challenging due to the complexity and incomplete characterization of tumor cell subpopulations. The heterogeneity of cells exhibiting stemness-related features, such as self-renewal and chemoresistance, fuels this complexity. Notch signaling is a known regulator of cancer stem cell (CSC) features in colorectal cancer (CRC), though the effects of its heterogenous signaling on CRC cell stemness are only just emerging. In this review, we discuss how Notch ligand-receptor specificity contributes to regulating stemness, self-renewal, chemoresistance and cancer stem cells heterogeneity in CRC.

The Impact of Cancer Stem Cells in Colorectal Cancer

“…The Notch signaling pathway (Figure 3) is crucial in regulating cell fate decisions, sustaining stem cell phenotypes, and contributing to tumor heterogeneity, particularly noted in CRC. This pathway's dysregulation, often due to mutations that lead to its constitutive activation, is associated with the progression of CRC, resistance to chemotherapy, and impacts regarding tumor heterogeneity [63][64][65].…”

“…Aberrant activation of Notch receptors in CRC points to their role in bolstering the stemness of CRC cells, complicating treatment resistance and disease recurrence [66]. Notch signaling components, particularly the HES gene family, are markedly upregulated in CSCs, fostering cell survival and impeding differentiation [63][64][65]67].…”

“…The pathway's influence extends to apoptosis inhibition, affecting tumor cell differentiation, proliferation, and maintaining CSC pluripotency. The pursuit of selective Notch pathway modulators, capable of targeting cancerous cells without harming healthy tissue, is critical, emphasizing the need for an in-depth understanding of this signaling pathway's role in CRC and the broader context of solid tumors [63][64][65]67].…”

“…The current therapeutic approaches targeting the Notch pathway, including gammasecretase inhibitors (GSI) and ADAM17 inhibitors, demonstrate promise in reducing colorectal CSCs' self-renewal and encouraging their differentiation. Specifically, targeting Notch ligands, like DLL4, with neutralizing antibodies has also shown therapeutic potential, offering insights into strategies that could disrupt CSC maintenance while mitigating broader pathway inhibition's side effects [63][64][65]. Furthermore, a study conducted by Anqi Lin et al regarding Notch has shown that mutations in the Notch signaling pathway significantly influence the efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) treatment.…”