Cancer Stem Cells

Cancer stem cells are a renewable population of cells within the tumor microenvironment. Similar to normal stem cells, cancer stem cells give rise to several cell types including other stem cells and progenitor cells which go on to differentiate guided by intrinsic programs and influenced by extrinsic cues. Within tumors, cancer stem cells are present in a small proportion, however they are responsible for tumor progression and metastasis and are associated with tumor recurrence after therapy. The origin of cancer stem cells is not fully elucidated, and several mechanisms have been proposed including cumulative mutations in normal stem cells or progenitor cells as drivers for cancer stem cell development. Additionally, de-differentiation mechanisms have been implicated in the origin of cancer stem cells as exemplified by the process of epithelial to mesenchymal transition (EMT) in carcinomas.

Tumor stromal cells influence the survival and self-renewal of Cancer Stem Cells

Tumor microenvironment and cancer stem cells, MTOR poster Novus Biologicals

The Tumor Microenvironment (TME) contains several cell types including endothelial cells, fibroblasts, mesenchymal stem cells and infiltrating immune cells as well as their derived soluble factors (e.g., cytokines and chemokines) which influence cancer stem cell properties and functions. In turn cancer stem cells, via various signaling mechanisms (e.g., IL-6, PDGF, VEGF and bFGF), modulate the activities and properties of stromal cells to ensure that the TME supports the survival of cancer stem cells, formation of new cancer stem cells and tumor expansion. The mTOR signaling pathway is implicated in the regulation of immune responses and angiogenesis within the TME thus shaping tumor progression and therapeutic responses.

Explore the role of mTOR in TME

VEGF expression in human angiosarcoma, IHC   CXCR1/IL-8 RA expression in human endometrial cancer, IHC

Immunohistochemistry-Paraffin: VEGF Antibody (VG1) [NB100-664] - FFPE human angiosarcoma tissue section using VEGF antibody (clone VG1). The endothelial cells of the blood vessels and most of the cancer cells showed strong positivity for VEGF protein.


CXCR1/IL-8 RA was detected in immersion fixed paraffin-embedded sections of human endometrial cancer tissue using Mouse Anti-Human CXCR1/IL-8 RA Monoclonal Antibody (Catalog # MAB330) at 5 µg/mL overnight at 4 °C. Specific staining was localized to cytoplasm.

Cancer Stem Cell Markers

Cancer stem cells are believed to underscore tumor heterogeneity and are themselves phenotypically diverse. Expression of specific stem cell markers (e.g., CD44, CD90, CD133) serve to isolate cancer stem cells in several solid tumors, but the specific combination of cellular markers expressed by cancer stem cell types is highly heterogeneous and dependent on the type of tumor and affected tissue. Significant variability in cancer stem cell phenotypes occurs within tumors which may arise through various mechanisms including clonal evolution, phenotype instability and resurgence from dormancy.

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Organ/Tissue Affected

Stem Cell Markers


Integrin beta 3/CD61 expression in human breast carcinoma tissue, IHC
CD61 NBP2-67416

CD44+, CD24-/low, ALDH1A1+, CD133+, CD49f+, CD61+

  • Increased expression of CD24 is associated with reduced stemness in breast cancer cells.
  • CD133 identifies cancer stem cells in triple-negative breast cancer and BRAC-1 tumors.

CD24 expression in human colon, IHC
CD24 Mab5248

Colorectal Adenocarcinoma: CD166+, CD44+, CD133+, CD24+, CD29+, ALDH1A1+, LGR5+, CXCR4+

  • CD24 expression may be associated with cancer stem cell differentiation.
  • Additional stem cell markers including LRIG1, TERT, HOPx and  DCLK1, associated with colorectal tumorigenesis require further characterization.

Head and Neck

CD44+, CD133+, ALDH1A1+, c-Met+


CD34+, CD38-, CD90-, CD117-, CD123+, TIM3+, CD47+, CD96+, CLECL1/CLL-1+, IL-1 RAcP+

  • Expression of each CD34 and CD38 is heterogeneous in leukemic stem cells.

alpha-Fetoprotein/AFP expression in Hep G2 human carcinoma cell line, Flow cytometry

Hepatocellular carcinoma (HCC): CD13+, CD24+, CD44+, CD90+, CD133+, OV6+

Cholangiocarcinoma (CCA): CD24+, CD44+, CD133+,  EpCAM+, CD274low, AFP+

  • Cholangiocarcinoma derived cancer stem cells may have high or low CD274 expression. High CD274 expression is associated with reduced stemness.
  • In liver cancer CD13+ identifies dormant cancer stem cells.
  • CD133 expression level does not always correlate with tumorigenicity in cholangiocarcinoma.

UPAR expression in human lung cancer tissue, IHC
uPAR AF807

Non-Small Cell Lung Carcinoma (NSCLC): CD133+, CD44+, ALDH1A1/ALDH2+, CD166+, BMI-1+

Small Cell Lung Carcinoma (SCLC): CD133+, ALDH1A1/ALDH2+, PODXL1+, uPAR+

  • Some lung tumor derived cancer stem cells may be CD133- or have transient CD133 expression.
  • ALDH1/2 expression in cancer stem cells may vary by specific lung region affected and cancer type (e.g., NSCLC vs SCLC).


CD44v6+, CD133+, CD166+, integrin alpha 2/α2β1high


CD44v6+, c-Met+, Tspan8+, integrin alpha 6/a6b4+, CXCR4+, CD133+, EpCAM+, Claudin7+

Melanotransferrin/CD228 expression in SK-Mel-28 human malignant melanoma cell line, Simple Western
Melanotransferrin MAB8175

ABCB5+, CD133+, CD20+, Nodal+, BMP4+, Melanotransferrin+, NGF r/CD271+

  • Several ATP-binding cassette or ABC family members are expressed in melanoma stem cells and are involved in mechanisms of drug resistance.

EMT and Cancer Stem Cells

The precise mechanisms leading to the development of cancer stem cells are not fully resolved. Several paths to stemness and tumor initiation have been proposed including:

  1. Cancer stem cells derive from normal stem cells through a process of mutagenesis
  2. Cancer stem cells derive from progenitor cells with a degree of self-renewal capacity through a process of mutagenesis
  3. Cancer stem cells derive through a process of de-differentiation from fully differentiated cells

The process of epithelial cell de-differentiation leading to a mesenchymal phenotype has been well described for various carcinoma types including hepatocellular, breast, pancreatic, colorectal carcinoma and more. In carcinoma, hypoxia represents a trigger for the induction of EMT programs leading to the development of stemness. Hypoxia, through the stabilization of HIF-1 alpha and HIF-2 alpha, is a driver for the development and maintenance of cancer stem cells.

Review Cellular Response to Hypoxia in Cancer

HIF signaling and cancer stem cell initiation and maintenance

Induction of HIF signaling, the principal transcriptional regulator of the hypoxic response, is associated with the expression of pluripotency markers, supporting the initiation and maintenance of stem cells. Several transcription factors induced in hypoxia are downstream of HIFs and play key roles in cancer cell-renewal including Oct4, NANOG, and Sox2.

Learn more about HIFs

Select References

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Cheah P. L., Li J., Looi L. M., Teoh K. H., Ong D. B., Arends M. J. (2018). DNA mismatch repair and CD133-marked cancer stem cells in colorectal carcinoma. PeerJ.

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Mikhail F., Popova A., Polyanskaya E., & Tjulandin S. (2017). Role of Stem Cells in Colorectal Cancer Progression and Prognostic and Predictive Characteristics of Stem Cell Markers in Colorectal Cancer. Current Stem Cell Research & Therapy.

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Romano, M., De Francesco, F., Gringeri, E., Giordano, A., Ferraro, G. A., Di Domenico, M., & Cillo, U. (2016). Tumor Microenvironment Versus Cancer Stem Cells in Cholangiocarcinoma: Synergistic Effects?Journal of Cellular Physiology.

Romano, M., De Francesco, F., Pirozzi, G., Gringeri, E., Boetto, R., Domenico, M. Di, … Cillo, U. (2015). Expression of cancer stem cell biomarkers as a tool for a correct therapeutic approach to hepatocellular carcinoma. Oncoscience. PMCID:PMC4468330

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Yamashita, T., & Wang, X. W. (2013). Cancer stem cells in the development of liver cancer. Journal of Clinical Investigation.