Boster Pathways-> Cancer & Stem Cell

Cancer & Stem Cell Signaling Pathway

A conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning, and organogenesis during embryonic development.

History of Cancer Stem Cells

The role of undifferentiated cells in cancer was first mentioned in the 1870s when there was a dispute between Rudolf Virchow (1821- 1902) and his student Julius Cohnheim (1839-1884). Cohenheim extensively expounded his theory of the origin of cancerous embryos in 1877. The theory assumed that the origin of tumor development must be attributed to the existence of "embryonic remains" in the body, and these "embryonic remains" were not used during development.

However, in the last fifteen years, many papers have often encouraged us to revisit the concept of cancer stem cells. This article mentions the key result of the new vision that led to cancer stem cells being viewed primarily as cells exhibiting greater epigenetic plasticity and greater variability of gene expression.

What are Cancer Stem Cells ?

Cancer stem cells (CSC) are a small group of cancer cells that have the ability to self-renew and differentiate into heterogeneous tumor cells and are believed to be involved in tumor occurrence, growth and recurrence. The first CSC population was discovered in human acute myeloid leukemia (AML), and they showed strong tumorigenicity in in vivo mouse models.

Normal Stem cell vs Cancer Stem Cells

Comparison of how CSC differs from normal stem cells.

Normal Stem Cells Cancer Stem Cells
Extensive but limited self-renewal capacity Extensive and Indefinite self-renewal capacity
Organogenic capacityTumorigenic capacity
Highly regulated self-renewal and differentiationHighly dysregulated self-renewal and differentiation
Rare in normal adult tissues Rare within tumors
Can be identified based on surface markers Similar type od surface markers as ordinary stem cells
Normal Karyotype Abnormal karyotype
Quiescent most of the time Less mitotically active than other cancer cells

Properties of Cancer Stem cells

Centered title marks the beginning of a new major section.

CSC has the same cellular and molecular mechanisms to regulate somatic stem cells; however, CSC lacks the control system needed to prevent uncontrolled proliferation. Although the specific origin of CSC is still controversial, there is evidence that they originate from stem cells that cannot control proliferation under abnormal conditions. Other proposed origins suggest that CSC may come from cell fusion between cancer cells and adult stem cells, gene transfer between somatic cells and cancer cells, or stem cell mutations. In addition, transformations may occur during tissue regeneration in response to inflammation, infection, exposure to toxins, and/or metabolic processes that may lead to mutations.

The self-renewal activity of SSCs is highly regulated by different signal pathways, but this strict regulation is lost in CSCs. In CSC, specific pathways such as Wnt / βcatenin, Jack / Stat, TGFβ, Notch and Sonic Hedgehog have been shown to be dysregulated.

What are Cancer Stem Cells ?

Cancer stem cells (CSC) are a small group of cancer cells that have the ability to self-renew and differentiate into heterogeneous tumor cells and are believed to be involved in tumor occurrence, growth and recurrence. The first CSC population was discovered in human acute myeloid leukemia (AML), and they showed strong tumorigenicity in in vivo mouse models.

Signaling pathways in normal stem cells and CSC

Hedgehog Signaling

The main players on the Hedgehog path are three secreted Hedgehog ligands — sonic, desert, and Indian — their cognate receptor Patched, transmembrane protein Patched, and three transcription factors of Glis1–3 that modulate pathway activation or repression (Gli was named for the identification and isolation of Gli1 from a glioma cell line). If unoccupied by the ligand, the patched receptor acts as a component inhibitor of Smoothened. In this condition, Gli3 and Gli2-R suppress target transcription of the gene (Gli2 in its repressor form). The repression is lifted when the ligand is bound to patch, allowing the Gli1 and Gli2-A (Gli2 in the activator form) transcriptional activators to promote the transcription of target genes.
In recent studies in which SMO genetic knockdown in CSCs led to the complete ablation of the malignant stem cells via just one in vivo-serial tumor passage, CSCs were similarly involved in the development of colon cancer. In the serial transition of tumors, the genesis of PTCH1 knockdown in CSCs has increased. These findings indicate that CSC column stemming and survival may need Hedgehog signaling, promoting the maintenance and development of tumors. In addition, significant levels of the Hedgehog Gli1 and Gli2 and HIP signaling genes, as compared with nonmetastatic controls, were discovered to be expressed by CSCs generated from colon cancer liver metastatic

However, Gli1 has been expressed solely in CSCs. Combined with experimental findings showing the increased CSC frequency with the development of the illness, this evidence indicates a possible rise in Hedgehog signaling activity as colon cancer develops. Indeed, the isolated CSCs exhibited greater SNAIL1 than nonmetastatic controls relative to the Gli1 target. Since SNAIL1 promotes the epithelial-mesenchymal transition, a process that is highly influenced by metastasization, the transcriptional gene data revealed the importance of Hedgehog Signals in the CSCs prometastatic function in this research.

WNT Signaling

CSC-mediated metastatic and maintenance of the CSC stem were linked with signaling from Wnt pathway . Flow cytometry research revealed that the Wnt signal proteins LEF1, cyclin D1, β-catenin, and TCF-4 have substantially increased in breast CSCs than non-stem cancer cell controls. Wnt-responsive gene transcription in the breasts has grown significantly in Wnt ligand therapy compared to non-standard cancer cell controls. Similarly, in CSCs, Wnt1 knockdown lowered the CD44, ALDH1, and Sca-1 expression of the genes and reduced the subset of breast cancer cells into the CSC. These results show that Wnt signs are needed for breast cancer stem maintenance. Finally, the Wnt gene expression study showed that TCF-4 expression levels in metastatic and nonmetastatic breast CSCs are substantially greater in former breast CSCs. These findings are consistent with previous studies that show a high proportion of CSCs between DVL breast cancer cells and that they show metastatic lymphatic propensity. These findings indicate that Wnt amplification in CSCs may be crucial in the spread of cancers.

Though the noncanonical Wnt signal may have a role in developing tumors, even though less researched than the canonical course via noncanonical Wnt ligand Wnt5a. Wnt5a can act as a tumor suppressor in an ErbB2-driven animal model. Its synthesis by luminous cells operates in paracrine ways to restrict the spread of tumor-initiating cells, which are situated. Disheveled2 (Dvl2) depletion reduced cell proliferation, encouraged differentiation, and hindered the development of the 3-dimensional neurosphere and tumorigenesis in glioma research. Dvl2 may rely on canonical and non-canonic Wnt signaling pathways for these regulatory effects.

Notch Signaling

Transmembrane proteins consist of notch ligands (DLL1, DLL3, DLL4, JAG1, and JAG2) and receivers (Notch1-4). When a ligand on one cell is bound to a receptor on the next cell, the pathway is triggered. This contact starts a proteolytic division of the receptor's cytoplasmic field by disintegrin and metalloproteinases (Adams), and β-secretase. This dual cleavage releases the Notch intracellular domain (NICD) into the cytoplasm. It stimulates the transcription of the target genes through the CBF1, Hairless suppressant LAG-1/recombination signal binding protein for the immunoglobulin KJ region (CSL/RBPJ).

The Notch pathway has been shown to control the tumor cell characteristics in various malignancies, including breast, colon, pancreatic, and lung cancers. However, evidence that Notch signaling has only lately been recognized as part of the control of tumor-inducing cells in cancer. In part, because activated signals by Notch may function as a tumor promoter or suppressor in distinct tissue depending on the environment, the ambiguity about the possible role in CSCs for Notch signaling remains. For instance, such as APC mutations in CRC, NOTCH1 activation mutations caused T-cell acute lymphoblastic leukemia. Notch's signaling in the intestinal crypts also showed that the cell's destiny is regulated. Notch signals were stopped, and cells were fully converted into differentiated goblet cells. Force adenomas produced by Apc mutations to differentiate the adenoma cells into goblin cells, which implies that Notch and Wnt activation may be required to preserve the undifferentiated CSC condition.

CSC stemming, patient-derived pancreatic CSCs showed that Notch1, Notch3, Jag1, Jag2, and the Notch target gene Hes1 are at greater levels. CSCs have reduced CSC's subpopulation and tumorsphere formation frequency using a gamma-secretase (β-sec) inhibitor. Similarly, a reduced and increasing CSC development in tumors with CSC's delta-serrate-Lag-2 peptide knockdown of Hes1 or CSCs therapy indicates that the signaling activity of Notch is needed for the CSC stumps. Death tests showed that y-secretase inhibitor therapy hindered the development of the cell cycle and promoted apoptosis, suggesting that the pathway Notch may assist pancreatic CSC stoning in enhancing cell survival.


Several key signaling pathways, including the RTK/RAS/MAP-Kinase (hence sometimes referred to as RTK-RAS for simplicity) pathway, PI3K/Akt signaling, and others, have been found as often genetically changed in cancer.

Cancer cells vary from normal cells in a variety of ways. Normal cells become malignant when a succession of mutations causes the cell to continue to grow and divide uncontrollably, and a cancer cell is, in some ways, an immortal cell. while Cancer stem cells are cancer cells that have features similar to normal stem cells, such as the capacity to give birth to all cell types observed in a specific cancer sample. As a result, CSCs are tumorigenic, possibly in contrast to other non-tumorigenic cancer cells.

Cancer stem cells (CSCs) are a tiny subset of cells seen inside tumors that exhibit cell surface markers such as CD44, CD24, and/or CD133. CSCs can self-renew and differentiate into non-tumorigenic cell offspring.

Several critical signaling pathways have been identified as often changed genetically in cancer, including Notch signalling, PTEN, WNT and hedgehog signaling pathway.

Separation of putative CSCs from the heterogeneous population isolated from a primary tumor. Flow cytometry is the technique used in identification. Sorting with flow cytometry allows the separation of marker positive cells from the marker negative cells.

Currently, there are no drugs known to kill cancer stem cells, However studies are ongoing to investigate possible drugs that could eventually eliminate cancer stems cells from human body.