Stem Cells, Cancer Stem-Like Cells, and Natural Products

 

 Permissions and Reprints

Abstract

Somatic stem cells can be found in many rapidly regenerating tissues, e.g., the skin, gastrointestinal mucosa, and hematopoietic system, but are also present at low numbers in non-regenerative organs such as the heart and brain. In these organs, somatic stem cells aid in normal tissue homeostasis and repair after injury as well as self-renewal and the generation of specific progenitor cells during differentiation. Cancer stem-like cells are a small subpopulation of self-renewing cells that are able to proliferate upon appropriate stimulation and differentiate into heterogeneous lineages in tumors. Modulation of the behavior of normal tissue stem cells and cancer stem-like cells is an emerging and thriving new field of research. The present review gives an overview of the state-of-the-art findings and highlights perspectives for future scientific developments and clinical application.

• References

• 1 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-111
  CrossrefPubMedGoogle Scholar
• 2 Weissman IL. Normal and neoplastic stem cells. Novartis Found Symp 2005; 265: 35-50 discussion: 50–54, 92–97
  PubMedGoogle Scholar
• 3 Murphy KM. Fate vs. choice: the immune system reloaded. Immunol Res 2005; 32: 193-200
  CrossrefPubMedGoogle Scholar
• 4 Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 2004; 118: 635-648
  CrossrefPubMedGoogle Scholar
• 5 Emre N, Coleman R, Ding S. A chemical approach to stem cell biology. Curr Opin Chem Biol 2007; 11: 252-258
  CrossrefPubMedGoogle Scholar
• 6 Dor Y, Melton DA. How important are adult stem cells for tissue maintenance?. Cell Cycle 2004; 3: 1104-1106
  PubMedGoogle Scholar
• 7 Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells – perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66: 9339-9344
  CrossrefPubMedGoogle Scholar
• 8 Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med 2007; 58: 267-284
  CrossrefPubMedGoogle Scholar
• 9 Hill RP, Perris R. “Destemming” cancer stem cells. J Natl Cancer Inst 2007; 99: 1435-1440
  CrossrefPubMedGoogle Scholar
• 10 Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15: 494-501
  CrossrefPubMedGoogle Scholar
• 11 Cozzio A, Passegué E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029-3035
  CrossrefPubMedGoogle Scholar
• 12 Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818-822
  CrossrefPubMedGoogle Scholar
• 13 Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets?. Carcinogenesis 2005; 26: 703-711
  CrossrefPubMedGoogle Scholar
• 14 Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 2005; 5: 899-904 Erratum in: Nat Rev Cancer 2005; 5: 995 Erratum in: Nat Rev Cancer 2005; 5: 995
  CrossrefPubMedGoogle Scholar
• 15 Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006; 7: 21-33
  CrossrefPubMedGoogle Scholar
• 16 Shmelkov SV, St Clair R, Lyden D, Rafii S. AC133/CD133/Prominin-1. Int J Biochem Cell Biol 2005; 37: 715-719
  CrossrefPubMedGoogle Scholar
• 17 Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983-3988 Erratum in: Proc Natl Acad Sci USA 2003; 100: 6890 Erratum in: Proc Natl Acad Sci USA 2003; 100: 6890
  CrossrefPubMedGoogle Scholar
• 18 Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030-1037
  CrossrefPubMedGoogle Scholar
• 19 Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007; 104: 973-978
  CrossrefPubMedGoogle Scholar
• 20 Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 2005; 11: 1154-1159
  PubMedGoogle Scholar
• 21 Schabath H, Runz S, Joumaa S, Altevogt P. CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci 2006; 119: 314-325
  CrossrefPubMedGoogle Scholar
• 22 Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, DʼAngelica M, Kemeny N, Lyden D, Rafii S. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 2008; 118: 2111-2120
  PubMedGoogle Scholar
• 23 Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004; 5: 738-743
  CrossrefPubMedGoogle Scholar
• 24 Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E. Defining the epithelial stem cell niche in skin. Science 2004; 303: 359-363
  CrossrefPubMedGoogle Scholar
• 25 Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7: 834-846
  CrossrefPubMedGoogle Scholar
• 26 Pantel K, Alix-Panabières C. The clinical significance of circulating tumor cells. Nat Clin Pract Oncol 2007; 4: 62-63
  PubMedGoogle Scholar
• 27 Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58: 1408-1416
  PubMedGoogle Scholar
• 28 Green SK, Frankel A, Kerbel RS. Adhesion-dependent multicellular drug resistance. Anticancer Drug Des 1999; 14: 153-168
  PubMedGoogle Scholar
• 29 Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93-106
  CrossrefPubMedGoogle Scholar
• 30 Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004; 4: 437-447
  CrossrefPubMedGoogle Scholar
• 31 Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer 2005; 5: 423-435
  CrossrefPubMedGoogle Scholar
• 32 Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004; 101: 14228-14233
  CrossrefPubMedGoogle Scholar
• 33 Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 2007; 67: 4827-4833
  CrossrefPubMedGoogle Scholar
• 34 Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 2007; 67: 3716-3724
  CrossrefPubMedGoogle Scholar
• 35 Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756-760
  CrossrefPubMedGoogle Scholar
• 36 Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut JA, Olive D. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 2000; 60: 4403-4411
  PubMedGoogle Scholar
• 37 Zaret KS. Using small molecules to great effect in stem cell differentiation. Cell Stem Cell 2009; 4: 373-374
  CrossrefPubMedGoogle Scholar
• 38 Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009; 8: 547-566
  CrossrefPubMedGoogle Scholar
• 39 Soprano DR, Teets BW, Soprano KJ. Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells. Vitam Horm 2007; 75: 69-95
  PubMedGoogle Scholar
• 40 Liang G, Taranova O, Xia K, Zhang Y. Butyrate promotes induced pluripotent stem cell generation. J Biol Chem 2010; 285: 25516-25521
  CrossrefPubMedGoogle Scholar
• 41 Reynertson KA, Charlson ME, Gudas LJ. Induction of murine embryonic stem cell differentiation by medicinal plant extracts. Exp Cell Res 2011; 317: 82-93
  CrossrefPubMedGoogle Scholar
• 42 Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, Chen K, Li Y, Liu X, Xu J, Zhang S, Li F, He W, Labuda K, Song Y, Peterbauer A, Wolbank S, Redl H, Zhong M, Cai D, Zeng L, Pei D. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 2010; 6: 71-79
  CrossrefPubMedGoogle Scholar
• 43 Hisha H, Yamada H, Sakurai MH, Kiyohara H, Li Y, Yu C, Takemoto N, Kawamura H, Yamaura K, Shinohara S, Komatsu Y, Aburada M, Ikehara S. Isolation and identification of hematopoietic stem cell-stimulating substances from Kampo (Japanese herbal) medicine, Juzen-taiho-to. Blood 1997; 90: 1022-1030
  PubMedGoogle Scholar
• 44 Lim J, Jeong SJ, Koh W, Han I, Lee HJ, Kwon TR, Jung JH, Kim JH, Lee HJ, Lee EO, Kim SH, Lee MH, Kim SH. JAK2/STAT5 signaling pathway mediates Bo-jung-bang-dock-tang enhanced hematopoiesis. Phytother Res 2011; 25: 329-337
  PubMedGoogle Scholar
• 45 Seo I, Kim SH, Lee JE, Jeong SJ, Kim YC, Ahn KS, Lu J, Kim SH. Ka-mi-kae-kyuk-tang oriental herbal cocktail attenuates cyclophosphamide-induced leukopenia side effects in mouse. Immunopharmacol Immunotoxicol 2011; 33: 682-690
  CrossrefPubMedGoogle Scholar
• 46 Boissy P, Andersen L, Abdallah BM, Kassem M, Plesner T, Delaissé JM. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005; 65: 9943-9952
  CrossrefPubMedGoogle Scholar
• 47 Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu SH, Cheng YC. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med 2010; 2: 45ra59
  CrossrefPubMedGoogle Scholar
• 48 Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 2011; 22: 799-806
  CrossrefPubMedGoogle Scholar
• 49 Krishnamurthy K, Wang G, Rokhfeld D, Bieberich E. Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide. Breast Cancer Res 2008; 10: R106
  CrossrefPubMedGoogle Scholar
• 50 Dai Z, Nair V, Khan M, Ciolino HP. Pomegranate extract inhibits the proliferation and viability of MMTV-Wnt-1 mouse mammary cancer stem cells in vitro . Oncol Rep 2010; 24: 1087-1091
  PubMedGoogle Scholar
• 51 Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 2010; 16: 2580-2590
  CrossrefPubMedGoogle Scholar
• 52 Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, Xing F, Fukuda K, Hirota S, Sugai T, Wakabayashi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Fujioka T, Tanji S, Mo YY, Cao D, Wilber AC, Watabe K. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res Treat 2011; 130: 387-398
  CrossrefPubMedGoogle Scholar
• 53 Li RJ, Ying X, Zhang Y, Ju RJ, Wang XX, Yao HJ, Men Y, Tian W, Yu Y, Zhang L, Huang RJ, Lu WL. All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. J Control Release 2011; 149: 281-291
  CrossrefPubMedGoogle Scholar
• 54 Casagrande F, Cocco E, Bellone S, Richter CE, Bellone M, Todeschini P, Siegel E, Varughese J, Arin-Silasi D, Azodi M, Rutherford TJ, Pecorelli S, Schwartz PE, Santin AD. Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of clostridium perfringens enterotoxin. Cancer 2011; 117: 5519-5528
  CrossrefPubMedGoogle Scholar
• 55 Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Hepatology 2011; 53: 160-170
  CrossrefPubMedGoogle Scholar
• 56 Volate SR, Kawasaki BT, Hurt EM, Milner JA, Kim YS, White J, Farrar WL. Gossypol induces apoptosis by activating p 53 in prostate cancer cells and prostate tumor-initiating cells. Mol Cancer Ther 2010; 9: 461-470
  CrossrefPubMedGoogle Scholar
• 57 Lu KH, Chen YW, Tsai PH, Tsai ML, Lee YY, Chiang CY, Kao CL, Chiou SH, Ku HH, Lin CH, Chen YJ. Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells. Childs Nerv Syst 2009; 25: 543-550
  CrossrefPubMedGoogle Scholar
• 58 Fong D, Yeh A, Naftalovich R, Choi TH, Chan MM. Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals. Cancer Lett 2010; 293: 65-72
  CrossrefPubMedGoogle Scholar
• 59 Hyun KH, Yoon CH, Kim RK, Lim EJ, An S, Park MJ, Hyun JW, Suh Y, Kim MJ, Lee SJ. Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells. Toxicol Appl Pharmacol 2011; 254: 32-40
  CrossrefPubMedGoogle Scholar
• 60 Gunn EJ, Williams JT, Huynh DT, Iannotti MJ, Han C, Barrios FJ, Kendall S, Glackin CA, Colby DA, Kirshner J. The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma. Leuk Lymphoma 2011; 52: 1085-1097
  CrossrefPubMedGoogle Scholar
• 61 Dorn DC, Kou CA, Png KJ, Moore MA. The effect of cantharidins on leukemic stem cells. Int J Cancer 2009; 124: 2186-2199
  CrossrefPubMedGoogle Scholar
• 62 Takeuchi M, Ashihara E, Yamazaki Y, Kimura S, Nakagawa Y, Tanaka R, Yao H, Nagao R, Hayashi Y, Hirai H, Maekawa T. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Sci 2011; 102: 591-596
  CrossrefPubMedGoogle Scholar
• 63 Blagosklonny MV. Target for cancer therapy: proliferating cells or stem cells. Leukemia 2006; 20: 385-391
  CrossrefPubMedGoogle Scholar
• 64 Schugar RC, Robbins PD, Deasy BM. Small molecules in stem cell self-renewal and differentiation. Gene Ther 2008; 15: 126-135
  CrossrefPubMedGoogle Scholar
• 65 Kawasaki BT, Hurt EM, Mistree T, Farrar WL. Targeting cancer stem cells with phytochemicals. Mol Interv 2008; 8: 174-184
  CrossrefPubMedGoogle Scholar
• 66 Harvey AL, Cree IA. High-throughput screening of natural products for cancer therapy. Planta Med 2010; 76: 1080-1086
  Article in Thieme ConnectPubMedGoogle Scholar
• 67 Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 2011; 22: 799-806
  CrossrefPubMedGoogle Scholar
• 68 Eichhorn T, Efferth T. P-glycoprotein and its inhibition by phytochemicals derived from Chinese herbs. J Ethnopharmacol in press
  PubMedGoogle Scholar
• 69 Wagner S, Hofmann A, Siedle B, Terfloth L, Merfort I, Gasteiger J. Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networks. J Med Chem 2006; 49: 2241-2252
  CrossrefPubMedGoogle Scholar
• 70 Bremner P, Heinrich M. Natural products as targeted modulators of the nuclear factor-kappaB pathway. J Pharm Pharmacol 2002; 54: 453-472
  CrossrefPubMedGoogle Scholar
• 71 Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat 2008; 111: 419-427
  CrossrefPubMedGoogle Scholar
• 72 Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 2003; 64: 382-394
  CrossrefPubMedGoogle Scholar
• 73 Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH, Efferth T. Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS One 2007; 2: e798
  CrossrefPubMedGoogle Scholar
• 74 Efferth T, Marschall M, Wang X, Huong SM, Hauber I, Olbrich A, Kronschnabl M, Stamminger T, Huang ES. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J Mol Med (Berl) 2002; 80: 233-242
  CrossrefPubMedGoogle Scholar
• 75 Bachmeier B, Fichtner I, Killian PH, Kronski E, Pfeffer U, Efferth T. Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. PLoS One 2011; 6: e20550
  CrossrefPubMedGoogle Scholar
• 76 Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002; 297: 1559-1561
  CrossrefPubMedGoogle Scholar
• 77 Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, Yee AS. Suppression of Wnt signaling by the green tea compound (−)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem 2006; 281: 10865-10875
  CrossrefPubMedGoogle Scholar
• 78 Byers S, Shah S. Vitamin D and the regulation of Wnt/beta-catenin signaling and innate immunity in colorectal cancer. Nutr Rev 2007; 65: S118-S120
  CrossrefPubMedGoogle Scholar
• 79 Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 2007; 121: 1360-1365
  CrossrefPubMedGoogle Scholar
• 80 Konkimalla VB, Blunder M, Korn B, Soomro SA, Jansen H, Chang W, Posner GH, Bauer R, Efferth T. Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells. Nitric Oxide 2008; 19: 184-191
  CrossrefPubMedGoogle Scholar
• 81 Cecchinato V, Chiaramonte R, Nizzardo M, Cristofaro B, Basile A, Sherbet GV, Comi P. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem Pharmacol 2007; 74: 1568-1574
  CrossrefPubMedGoogle Scholar
• 82 Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006; 66: 7445-7452
  CrossrefPubMedGoogle Scholar