| Main Signaling Pathways | Key Physiologic Functions | Dysregulation in Signaling Pathways | Role in Cancer Development | Potential Implications in Oncology |
|---|---|---|---|---|
|
NANOG [4] a transcription factor |
a regulator of ESCs self-renewal; an inhibitor of SCs differentiation; a regulator of SCs pluripotency; a regulator of cell-fate specification, proliferation, apoptosis; |
overexpressed in various cancers (e.g.: esophagus, colon, ovary, prostate, breast, & brain); overexpression correlated with advanced stages of malignancy and poor prognosis. |
clonogenic growth, tumorigenicity, transformation, invasiveness, metastasis and therapeutic resistance; a part of regulatory network, communicating with other transcription factors in cancer cells |
a potential target for oncology therapy (e.g., gastrointestinal malignant tumors) |
|
Wnt/β-catenin [5] a signaling regulatory network regulated by the microenvironment |
a role in embryogenesis -the regulation of apoptosis in developing cells; the regulation of tissue homeostasis and SC function in adult tissues; |
contributes to inducing epithelial-to-mesenchymal transition (EMT), an early step in the invasion-metastases, relevant to poor clinical outcomes | aberrant Wnt signaling regulation in GI cancers (e.g: colon, hepatocellular) &, medulloblastoma | inhibition of Wnt/β-catenin signaling can affect cancer cell growth and survival |
|
Hedgehog (HH) [6, 7, 17] a developmental pathway, which can be altered by CSCs in tumorigenesis |
a role in cell differentiation & organogenesis during the embryonic development; involved in the development & maintenance of intestinal tissue; |
dysregulated in GI cancers & in basal-cell carcinoma. | inhibitors of HH signaling are being explored in clinical trials for basal-cell carcinoma & gastrointestinal cancers [7, 8] | Vismodegib [7] small-molecule inhibitor of the HH pathway, associated with tumor responses in patients with advanced or metastatic basal-cell carcinoma; HH inhibition can reverse ChT resistance in CD44(+) cells; combining ChT with HH inhibition may only be effective in gastric tumors with high CD44 levels [8] |
|
Notch [9] the Notch gene encodes a receptor; Notch signaling is crucial in the cell development by maintaining the self-renewal potential of some tissues & inducing cell differentiation of others |
signaling between Notch receptors and ligands influences cell differentiation and acts as a tumor suppressor (promoting cell differentiation & inhibiting proliferation) | in order to cause cancer, Notch requires the cooperation of oncoproteins that can override the G1-S checkpoint. | Notch signaling can promote or suppress tumor growth, in communication with other signal-transduction pathways (e.g.: Hedgehog, Wnt, or the factors from tumor micro- environment) | Notch functions as an oncogene (e.g., in hematopoietic cells); aberrant expression of Notch can promote T-cell leukemia; |
|
STAT3 [10-12] a specific set of genes, including those involved in Jak-STAT signaling pathway [10] |
a latent cytoplasmic transcription factor, activated by growth factors or cytokines; provides survival signals & suppresses apoptosis |
an activator of transcription & regulator of cancer cell stemness; influences cell migration (necessary for invasion & metastatic spread); STAT3 enables CSCs to survive, proliferate, metastasize, and evade the immune system; STAT3 activation protects tumor cells from immune surveillance & augments surviving tumor cells invading distant organs; Jak-STAT activation is a characteristic of putative breast CSCs |
overexpression of STAT3 leads to development of some cancers (e.g.: breast, lung, prostate, colorectal, hepatic, & hematological) Targeting STAT3 activation can stop tumor growth & metastasis, without affecting normal cells; STAT3 is an important molecular target for anticancer therapies [11] |
Napabucasin [12] a STAT3 inhibitor that can be a novel treatment strategy for the advanced prostate cancer (e.g., castration-resistant prostate cancer (CRPC) [12] napabucasin [11] has been investigated in colorectal, gastric, gastroesophageal cancer (Phase 3 RCT) |
|
PTEN [13] PI3K/Akt/mTOR a signaling pathway [13] |
PTEN pathway helps regulate the proliferative rate & number of intestinal SCs; | PI3K/Akt/mTOR pathway is a key regulator for cancer, linked with the CSCs | PI3K/Akt/mTOR pathway can be a promising target for development of CSC-targeted agents. | small molecule inhibitors of PI3K/Akt/mTOR signaling pathway have clinical potential in CSCs. |