Cancer stem cells (CSCs) are cancer cells that initiate tumor formation, growth, and metastasis. These cells contribute to these processes by remaining undifferentiated and self-renewing — features that are largely specified by the expression of select transcription factors. In addition to transcription factors, cancer stem cells also upregulate certain surface markers, which can be used to distinguish cancer stem cells from other cancer cells. Still, more markers of stemness—the capability of a cell for self-renewal and differentiation—can also be found in the cytoplasm of cancer cells. Some markers are common to a wide variety of tumor types (“inclusive markers”), whereas others are more specific (“exclusive markers”). This article summarizes the most commonly described cancer stem cell markers in each of these categories.

Inclusive Cancer Stem Cell Markers

There are no universal cancer stem cell markers that can identify cancer stem cells and only cancer stem cells of every cancer. That is because the few stemness markers that are shared by all cancer types are also shared by non-cancer cells (including normal stem cells and various differentiated cell types). The Yamanaka (or pluripotency) factors OCT4, MYC, KLF4, and SOX2 are prime examples of markers that denote stemness, cancer or not. Together, these four transcription factors induce pluripotency by regulating a variety of developmental signaling pathways such as the Notch and Wnt signaling pathways. Notch and Wnt signaling can also serve as markers of stemness in multiple cancers, including breast and colorectal cancers. NANOG and SALL4 are further examples of a pluripotency factor also found in cancer stem cells.

Figure image: Cancer stem cell markers (CSCs) are often shared by other cell types, including other stem cells (stemness markers), differentiated cells, and tissue-specific cancer cells.

Cancer stem cells also share markers with differentiated (non-stem) cell types. For example, the lymphocyte markers CD19, CD24, CD38, and CD44 have also been detected in the stem cell populations of several cancers. In fact, the glycoprotein CD44 has been detected on the stem cells of most cancers, including breast, pancreatic, prostate, colorectal, ovarian, lung, liver, head/neck, blood, bladder, gastric, brain, bone, and cervical cancers.

Other such markers include CD24 and CD90 (THY1), both of which are expressed in neurons and lymphocytes as well as blood, liver, breast, brain, lung, head/neck, and gastric cancer stem cells; and the epithelial cell markers CD133 (PROM1) and EPCAM, which are also expressed by brain, colorectal, lung, liver, prostate, pancreatic, breast, ovarian, and gastric cancer stem cells.

Exclusive Cancer Stem Cell Markers

Exclusive cancer stem cell markers are those that label the stem cells of only one or two cancers. Exclusive refers to expression among different cancer stem cell populations, as some of these markers may also be expressed by analogous normal stem cell populations. These markers are outlined below by cancer type.

Bladder cancer. CD47 is a marker of bladder cancer stem cells, although it can be found on virtually all bladder cells, albeit at lower expression levels. This marker has been shown to promote bladder cancer engraftment, and its silencing promotes macrophage phagocytosis of bladder cancer cells. Bladder cancer stem cells are also CD66clo (CEACAM6lo).

Blood cancers. The first cancer stem cell markers to be confirmed in vivo were of the blood cancer acute myeloid leukemia, where CD34+CD38- hematopoietic stem cells were discovered to promote AML tumorigenesis. Despite being mostly exclusive to blood cancers, these markers are also expressed by noncancerous hematopoietic stem cells. IL3RA is another blood cancer stem cell marker that labels noncancerous hematopoietic stem cells. HAVCR2 (TIM-3), however, marks cancerous hematopoietic stem cells but not noncancerous ones, enabling their differentiation.

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Brain cancers. Initially discovered in neural embryonic progenitors, FUT4 is a gene that encodes the enzyme responsible for synthesizing the Lewis X (CD15) carbohydrate. As such, both markers can be used to identify brain cancer stem cells.

Breast cancer. Stem cells in breast cancer share many markers with the stem cells of other cancer types, such as ITGA6 (CD49f) and CD90. ITGB3 (CD61), however, is a breast cancer-specific stem cell marker.

Colorectal cancer. While no marker uniquely labels colorectal cancer stem cells, the glycoprotein dipeptidyl-peptidase 4 (CD26), encoded by DPP4, is perhaps the most exclusive of stemness in colorectal cancer, where it promotes metastasis.

Gastric cancer. Exclusive stem cell markers of gastric cancers include LINGO2, LETM1, and MSI2. LINGO2 and LETM1 regulate the Akt signaling and contribute to cancer processes like angiogenesis, metastasis, and tumorigenicity. MSI2 regulates similar processes. Silencing LINGO2 also silences the pluripotency factor and inclusive cancer stem cell marker OCT4. The brain cancer stem cell marker Lewis X/CD15 is also associated with gastric cancer stem cells.

Head & neck cancer. The primary exclusive cancer stem cell marker of head and neck cancer is NGFR (CD271). LGR5 (GPR49), while also present on the same cells, is expressed by colorectal, gastric, and breast cancer stem cells.

Liver cancer. The oncofetal marker (one that is expressed in embryonic and cancerous but not adult tissues) AFP can be used to identify liver cancer stem cells. This marker is a secreted biomarker of malignant liver cancer that can be detected in blood.

Lung cancer. Like blood cancer stem cells, lung cancer stem cells express CD34. PLAUR (CD87) can be used to distinguish blood cancer stem cells from lung cancer stem cells.

Melanoma. In addition to marking head & neck cancer stem cells, NGFR (CD271) is a well-established cancer stem cell marker that maintains stemness in melanoma cells. The keratinocyte marker ABCB5 and the lymphocyte marker CD20 (MS4A1) are additional markers of stemness in melanoma.

Ovarian and cervical cancers. Another normal stem cell marker, ENG (CD105) identifies both ovarian and cervical cancer stem cells. The marker is also associated with angiogenesis, especially in and around tumors.

Prostate cancer. Prostate cancer stem cells are CD44+CD133+HNRNPA2B1hi, mirroring their highly proliferative yet noncancerous CD133+HNRNPA2B1hi epithelial cousins in the prostate. Although CD44 and CD133 are found in many cancer stem cell populations, HNRNPA2B1 is limited to those of prostate cancer. CD151 is another marker exclusively expressed by prostate cancer stem cells.

Table of cancer stem cell markers

The table below lists human and mouse cancer stem cells markers as described in recent literature. The majority of proteins listed are either glycoprotein markers or transcription factors, but other defining markers, such as receptors, binding proteins, and even signaling pathways, are also included. Accompanying each marker are links to relevant antibodies and ELISA kits, as these immunodetection tools are routinely used in cell characterization studies via flow cytometry and immunostaining. The associated products are offered by a variety of manufacturers and can serve as a useful reference for cancer stem cell identification and profiling.

GeneSynonymsMarker TypeProtein TypeLocalizationSize (kDa)ReferenceAntibodiesELISA Kits
CD44   Breast, Pancreatic, Prostate, Colorectal, Ovarian, Lung, Liver, Head/Neck, Blood, Bladder, Gastric, Brain, Cervix Membrane protein Cell Membrane 81.5 1,2,3,4,5,6 CD44 antibodies CD44 ELISA
CD24   Breast, Pancreatic, Colorectal, Ovarian, Lung, Head/Neck, Gastric, Liver Membrane protein Cell Membrane 8.1 1,2,3,4,5,6 CD24 antibodies CD24 ELISA
ALDH1A1   Breast, Colorectal, Prostate, Ovarian, Lung, Liver, Head/Neck, Gastric, Leukemia Enzyme Cytoplasm 54.9 1,2,3,5,6 ALDH1A1 antibodies ALDH1A1 ELISA
PROM1 CD133 Pancreatic, Prostate, Brain, Liver, Colorectal, Ovarian, Melanoma, Lung, Head/Neck, Brain, Gastric, Renal Membrane protein Cell Membrane 97.3 1,2,3,4,5,6 PROM1 antibodies PROM1 ELISA
EPCAM TROP1, ESA Pancreatic, Colorectal, Breast, Ovarian, Liver, Lung, Gastric, Brain Adhesion molecule Cell Membrane 35 1,2,3,4,5,6 EPCAM antibodies EPCAM ELISA
HNRNPA2B1 ɑ2β1 Prostate Nuclear protein Nucleus 37.5 1,2 HNRNPA2B1 antibodies HNRNPA2B1 ELISA
FUT4 SSEA-1 Brain Enzyme Cell Membrane 59.1 1,2 FUT4 antibodies FUT4 ELISA
CD34   Blood, Lung Membrane protein Cell Membrane 40.7 1,2,3,4,6 CD34 antibodies CD34 ELISA
CD38   Blood Membrane protein Cell Membrane 34.4 1,3,4,6 CD38 antibodies CD38 ELISA
ITGB3 CD61 Breast Adhesion molecule Cell Membrane 87.1 2,5 ITGB3 antibodies ITGB3 ELISA
THY1 CD90 Blood, Liver, Breast, Brain, Lung, Head/Neck, Gastric Membrane protein Cell Membrane 18 1,2,3,4,5,6 CD90 antibodies CD90 ELISA
KIT c-kit, CD117 Blood, Ovarian, Lung, Liver Receptor Cell Membrane 109.8 1,2,3,5,6 KIT antibodies KIT ELISA
IL3RA CD123 Blood Receptor Cell Membrane 39.1 1,3,5 CD123 antibodies CD123 ELISA
ITGA6 CD49f Liver, Breast, Brain, Prostate Adhesion molecule Cell Membrane 126.7 1,2,3,5,6 ITGA6 antibodies ITGA6 ELISA
ALCAM CD166 Colorectal, Melanoma, Prostate, Lung Adhesion molecule Cell Membrane 65.2 1,2,3,4,5 ALCAM antibodies ALCAM ELISA
ITGB1 CD29 Colorectal, Breast, Cervix Adhesion molecule Cell Membrane 86.4 1,2,3,4,5,6 ITGB1 antibodies ITGB1 ELISA
DPP4 CD26 Colorectal, Blood Enzyme Cell Membrane, Secreted 88.3 1,3-5 DPP4 antibodies DPP4 ELISA
LGR5   Colorectal, Head/Neck, Breast, Gastric Receptor Cell Membrane 100 1,2,3,5 LGR5 antibodies LGR5 ELISA
ANPEP CD13 Breast, Liver, Cervix Enzyme Cell Membrane 109.5 2,4 ANPEP antibodies ANPEP ELISA
NANOG   Breast, Brain, Ovarian, Lung, Colorectal, Prostate, Gastric, Leukemia Transcription Factor Nucleus 34.7 2,3,5 NANOG antibodies NANOG ELISA
KLF4   Breast, Brain, Colorectal, Leukemia, Prostate Transcription Factor Nucleus 54.7 2,3 KLF4 antibodies KLF4 ELISA
NES Nestin Brain, Melanoma, Pancreatic Filament protein Cytoplasm 177.5 2,3 Nestin antibodies Nestin ELISA
SOX2   Colorectal, Brain, Pancreatic, Prostate, Ovarian, Melanoma, Lung, Breast, Gastric, Leukemia Transcription Factor Nucleus 34.4 2,3,5 SOX2 antibodies SOX2 ELISA
MSI1 Musashi-1 Brain, Colorectal Binding protein Cytoplasm 39.2 1,2,3 MSI1 antibodies MSI1 ELISA
BMI1   Brain, Lung, Head/Neck, Leukemia, Breast, Colorectal, Prostate, Pancreatic Binding protein Nucleus 37 2,3,5 BMI1 antibodies BMI1 ELISA
CXCR4   Pancreatic, Breast, Brain, Gastric Receptor Cell Membrane 39.7 2,3,5 CXCR4 antibodies CXCR4 ELISA
POU5F1 OCT4 Ovarian, Melanoma, Bladder, Pancreatic, Prostate, Lung, Breast, Liver, Leukemia Transcription Factor Nucleus 38.6 2,3,5 POU5F1 antibodies POU5F1 ELISA
MS4A1 CD20 Melanoma, Blood Membrane Protein Cell Membrane 33.1 2,3,4,6 MS4A1 antibodies MS4A1 ELISA
ABCB5   Melanoma Transporter Cell Membrane 138.7 2,4 ABCB5 antibodies ABCB5 ELISA
NGFR CD271 Melanoma, Head/Neck Receptor Cell Membrane 45.2 2,4,6 NGFR antibodies NGFR ELISA
PLAUR CD87 Lung Receptor Cell Membrane 37 2,5 PLAUR antibodies PLAUR ELISA
AFP   Liver Binding protein Secreted 68.7 2,5 AFP antibodies AFP ELISA
HAVCR2 TIM3 Blood Receptor Cell Membrane 33.4 3,5 TIM-3 antibodies TIM-3 ELISA
SALL4   Blood, Breast, Colorectal, Ovarian, Prostate Transcription Factor Cytoplasm, Nucleus 112.3 3,5 SALL4 antibodies SALL4 ELISA
CD15* Lewis X Gastric, Brain Carbohydrate Antigen Cell Membrane   3,4,6 CD15 antibodies CD15 ELISA
CD19   Blood Membrane Protein Cell Membrane 61.1 3,4 CD19 antibodies CD19 ELISA
ENG CD105 Ovarian, Cervix Membrane Protein Cell Membrane 70.6 3,4 ENG antibodies ENG ELISA
CD151   Prostate Membrane Protein Cell Membrane 28.3 3,4 CD151 antibodies CD151 ELISA
LINGO2   Gastric Binding protein Cell Membrane 68.1 5 LINGO2 antibodies LINGO2 ELISA
LETM1   Gastric, Colorectal Membrane Protein Cytoplasm 83.4 5 LETM1 antibodies LETM1 ELISA
MSI2   Gastric Binding protein Cytoplasm 35.2 5 MSI2 antibodies MSI2 ELISA
CD47   Leukemia, Bladder Membrane Protein Cell Membrane 33.1 3 CD47 antibodies CD47 ELISA
CEACAM6 CD66c Bladder Adhesion molecule Cell Membrane 37.2 3 CEACAM6 antibodies CEACAM6 ELISA

Note: *This marker is a carbohydrate antigen. Information on Protein Type, Localization, and Size (kDa) obtained from UniProt.org (for human genes only). 

References

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4. Gopalan V, Islam F, Lam AK. Surface Markers for the Identification of Cancer Stem Cells. Methods Mol Biol. 2018;1692:17-29. doi:10.1007/978-1-4939-7401-6_2

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