Journal of Cancer Sciences

Download PDF
Editorial Article

Targeting Pancreatic Cancer Stem Cells

Xiangwei Xiao*

  • Department of Surgery, Children’s Hospital of Pittsburgh, USA

*Address for Correspondence: Xiangwei Xiao, M.D., Ph.D. Assistant Professor of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, 4401 Penn Ave, PA15238, USA, Tel: +14126929210; Fax: +4126923466; E-mail:
Xiao X. Targeting Pancreatic Cancer Stem Cells. J Cancer Sci. 2015;2(1): 3.
Copyright © 2015 Xiao. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Cancer Sciences | ISSN: 2377-9292 | Volume: 2, Issue: 1
Submission: 05 February 2015 | Accepted: 09 February 2015 | Published: 11 February 2015

Carcinomas of an epithelial-origin account for the majority of all malignant cancers worldwide. As the most common pancreatic cancer, Pancreatic Ductal Adeno Carcinoma (PDAC) is a carcinoma with an extremely high lethality [1-3]. Compared to other cancers originating in the digestive system, the therapeutic outcome of PDAC treatment is the least promising, largely resulting from a lack of symptoms at the early stages of PDAC and a lack of sensitive diagnostic biomarkers and effective treatments [1-3].

Cancer stem cells (CSCs) are cancer cells with characteristics of stem cells. CSCs are highly tumorigenic, and are recognized to be responsible for tumor outgrowth; cancer metastases, chemotherapeutic resistance, and cancer relapse after resection [1-3]. Treatments targeting CSCs thus are highly attractive for their potential to more effectively treat rapidly growing, highly metastatic cancers [1-3]. Great efforts have been made to identify and isolate CSCs in various cancers. Of note, past studies have suggested that CSCs do exist in PDAC [1-3].

Although the gold-standard for identification of CSCs may require tumorigenecity in vivo at the single cell level, current studies use cell replication potential, tumor sphere formation in vitro and tumor formation in serial transplantation with a limited number of tumor cells to characterize CSCs or CSC-like cells [1-3].

Cell surface markers have been used for isolation of CSCs by flow cytometry. Among these markers, prominin-1 (CD133) is probably best studied [4-6], and has been shown to specifically label CSCs in PDAC [7]. CD133-postive cells from freshly resected human tumor samples were highly tumorigenic and highly resistant to standard chemotherapy [7]. Tumor formation in immunodeficient mice could be detected after implantation of as few as 500 CD133-positive cells [7]. The formed tumors morphologically and histological resembled the parental tumors [7]. In vitro, CD133-positive cells formed tumor spheres in serum-free suspension culture [7]. These data demonstrate a CSC-like self-renewal potential of these cells, in vitro and in vivo. Further, a subpopulation of CD133+/CXCR4+ cells appeared to be essential for tumor migration [7]. Clinical support for CD133 as a CSC marker in PDAC was later obtained from an independent study, showing a correlation of serum CD133 levels with patients’ therapeutic outcomes [8]. Here, a relationship between CD133 levels and vascular endothelial growth factor (VEGF)-C, which regulates lymphatic metastasis, has been indicated [8].

Another well-studied CSC marker for PDAC is CD44 [9,10]. Li et al. identified a highly tumorigenic subpopulation of PDAC cells expressing the cell surface markers CD44, CD24, and epithelial specific antigen (ESA), using a xenograft model in which primary human PDAC cells were implanted into immune compromised mice [10]. A 100-fold increases in tumorigenic potential was achieved with CD44+CD24+ESA+ cells, compared with triple negative cells [10]. Moreover, in this study, the signaling molecule sonic hedgehog and the polycomb gene family member Bmi-1 seemed to be activated in CSC-like cells [10], which was later confirmed by an independent study that suggests involvement of hedgehog activation in CSCs in PDAC [11]. In addition, the receptor for hepatocyte growth factor (HGFR), Met, has recently been shown to enrich CSCs when used together with CD44 or CD133 [12].

Apart from using CD44 and CD133 as CSC markers for PDAC, other approaches have been taken for the enrichment of CSCs. Aldefluor is a feature of increased cellular aldehyde dehydrogenase (ALDH) activity. Increased activity of ALDH1, a detoxifying enzyme responsible for the oxidation of intracellular aldehydes [13,14], has also been used in identification of stem/progenitor cells or CSCs [15-20]. Nevertheless, ALDH/aldefluor-based enrichment of CSCs seemed to be less efficient. ALDH1-positive cells have been shown to be only 10 times more clonogenic than negative counterparts in PDAC [21-23]. Moreover, recent evidence suggests the presence of aldefluor-positive cells in other cell types in the pancreas, such as proliferating pancreatic beta cells [24,25].

Proteasome activity has recently been used to identify CSCs in PDAC [26]. Adikrisna et al. expressed a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) in selective PDAC cell lines, and isolated CSCs by taking advantage of the fluorescent Gdeg accumulation in CSCs resulting from low 26S proteasome activity [26]. With the help of this system, they were able to identify and isolate Gdeg-high cells as CSC-like cells, by tumor sphere formation, asymmetric division-feature, and tumor formation in mice with as few as 10 Gdeg-high cells [26].

Finally, epithelial-to-mesenchymal transition (EMT), in which a cell switches from an epithelial phenotype to a mesenchymal phenotype, provides the fundamental machinery for tumor invasion, migration and metastases. A putative relationship between EMT and CSCs has already been well established [27-29]. Indeed, EMT confers many important signal passages that are associated with properties of CSCs. On the other hand, CSCs are found to express high levels of EMT-associated genes [30,31]. Transforming growth factor β (TGFβ) receptor signaling plays a key role in pancreas development and physiology [32-35], and a prominent role in pancreatitis and EMT [36,37]. In line with this notion, past studies have effectively demonstrated the involvement of TGFβ receptor signaling-mediated EMT in the carcinogenesis of PDAC [38,43]. Future experiments may study the possibility of using EMT-associated markers to identify CSCs in PDAC.In summary, although previous approaches have significantly improved our understanding and identification of CSCs in PDAC, none of the methods for CSC purification is capable of identifying single tumorigenic cells. Further effort is required to improve current strategies for CSC identification in PDAC.


This work was supported by the Cochrane-Weber endowed Fund in Diabetes Research (XX, NO19831).


  1. Abel EV, Simeone DM (2013) Biology and clinical applications of pancreatic cancer stem cells. Gastroenterology 144: 1241-1248.
  2. Sergeant G, Vankelecom H, Gremeaux L, Topal B (2009) Role of cancer stem cells in pancreatic ductal adenocarcinoma. Nat Rev Clin Oncol 6: 580-586.
  3. Lee CJ, Dosch J, Simeone DM (2008) Pancreatic cancer stem cells. J Clin Oncol 26: 2806-2812.
  4. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, et al. (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 118: 2111-2120.
  5. Crea F, Fornaro L, Masi G, Falcone A, Danesi R, et al. (2011) Faithful markers of circulating cancer stem cells: Is CD133 sufficient for validation in clinics? J Clin Oncol 29: 3487-3488.
  6. Huttner WB (2010) Prominin-1/cd133 and the cell biology of (cancer) stem cells. JSRM 6: 37.
  7. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, et al. (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1: 313-323.
  8. Maeda S, Shinchi H, Kurahara H, Mataki Y, Maemura K, et al. (2008) CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer 98: 1389-1397.
  9. Zhu J, He J, Liu Y, Simeone DM, Lubman DM (2012) Identification of glycoprotein markers for pancreatic cancer CD24+CD44+ stem-like cells using nano-LC-MS/MS and tissue microarray. J Proteome Res 11: 2272-2281.
  10. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, et al. (2007) Identification of pancreatic cancer stem cells. Cancer Res 67: 1030-1037.
  11. Li SH, Fu J, Watkins DN, Srivastava RK, Shankar S (2013) Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol Cell Biochem 373: 217-227.
  12. Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, et al. (2011) c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 141: 2218-2227.
  13. Duester G (2000) Families of retinoid dehydrogenases regulating vitamin a function: Production of visual pigment and retinoic acid. Eur J Biochem 267: 4315-4324.
  14. Magni M, Shammah S, Schiro R, Mellado W, Dalla-Favera R, et al. (1996) Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 87: 1097-1103.
  15. Armstrong L, Stojkovic M, Dimmick I, Ahmad S, Stojkovic P, et al. (2004) Phenotypic characterization of murine primitive hematopoietic progenitor cells isolated on basis of aldehyde dehydrogenase activity. Stem Cells 22: 1142-1151.
  16. Hess DA, Craft TP, Wirthlin L, Hohm S, Zhou P, et al. (2008) Widespread nonhematopoietic tissue distribution by transplanted human progenitor cells with high aldehyde dehydrogenase activity. Stem Cells 26: 611-620.
  17. Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, et al. (2004) Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood 104: 1648-1655.
  18. Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, et al. (2006) Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood 107: 2162-2169.
  19. Silva IA, Bai S, McLean K, Yang K, Griffith K, et al. (2011) Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 71: 3991-4001.
  20. Ma I, Allan AL (2011) The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 7: 292-306.
  21. Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, et al. (2010) Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 102: 340-351.
  22. Vizio B, Mauri FA, Prati A, Trivedi P, Giacobino A, et al. (2012) Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma. Oncol Rep 27: 69-76.
  23. Kim MP, Fleming JB, Wang H, Abbruzzese JL, Choi W, et al. (2011) ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One 6: e20636.
  24. Liu Y, Jiang X, Zeng Y, Zhou H, Yang J, et al. (2014) Proliferating pancreatic beta-cells upregulate ALDH. Histochem Cell Biol 142: 685-691.
  25. Zhang L, Wang L, Liu X, Zheng D, Liu S, et al. (2014) ALDH expression characterizes G1-phase proliferating beta cells during pregnancy. PLoS One 9: e96204.
  26. Adikrisna R, Tanaka S, Muramatsu S, Aihara A, Ban D, et al. (2012) Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology 143: 234-245.
  27. Biddle A, Mackenzie IC (2012) Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev [Epub ahead of print].
  28. Kong D, Li Y, Wang Z, Sarkar FH (2011) Cancer stem cells and epithelial-to-mesenchymal transition (EMT)-phenotypic cells: Are they cousins or twins? Cancers 3: 716-729.
  29. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 29: 4741-4751.
  30. Bessede E, Staedel C, Acuna Amador LA, Nguyen PH, Chambonnier L, et al. (2014) Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes. Oncogene 33: 4123-4131.
  31. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, et al. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704-715.
  32. El-Gohary Y, Tulachan S, Guo P, Welsh C, Wiersch J, et al. (2013) Smad signaling pathways regulate pancreatic endocrine development. Dev Biol 378: 83-93.
  33. El-Gohary Y, Tulachan S, Wiersch J, Guo P, Welsh C, et al. (2014) A smad signaling network regulates islet cell proliferation. Diabetes 63: 224-236.
  34. Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, et al. (2013) TGFβ receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes 62: 1217-1226.
  35. Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, et al. (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A 111: E1211-1220.
  36. Hahm KB, Im YH, Lee C, Parks WT, Bang YJ, et al. (2000) Loss of TGF-beta signaling contributes to autoimmune pancreatitis. J Clin Invest 105: 1057-1065.
  37. Sanvito F, Nichols A, Herrera PL, Huarte J, Wohlwend A, et al. (1995) TGF-beta 1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Commun 217: 1279-1286.
  38. Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, et al. (2010) Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 403: 380-384.
  39. Truty MJ, Urrutia R (2007) Basics of TGF-beta and pancreatic cancer. Pancreatology 7: 423-435.
  40. Wagner M, Kleeff J, Friess H, Buchler MW, Korc M (1999) Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 19: 370-376.
  41. Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, et al. (1999) The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18: 5363-5372.
  42. Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, et al. (1993) Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105: 1846-1856.
  43. Friess H, Yamanaka Y, Buchler M, Berger HG, Kobrin MS, et al. (1993) Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res 53: 2704-2707.