Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway
- 1.2k Downloads
Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell’s EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway.
KeywordsMesenchymal stem cells Breast cancer Proliferation Mammosphere EGF Xenograft PI3K/Akt
This study was supported by National High Technology Research and Development Program of China (No:2006AA02A107), the Major State Basic Research Program of China (No:2009CB521704, 2010CB945504), and National Nature Science Foundation of China, (30873031, 30971145).
Conflict of interest
The authors confirm that there are no conflicts of interest.
- 7.Kurtova AV, Balakrishnan K, Chen R, Ding W, Schnabl S, Quiroga MP, Sivina M, Wierda WG, Estrov Z, Keating MJ, Shehata M, Jager U, Gandhi V, Kay NE, Plunkett W, Burger JA (2009) Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood 114(20):4441–4450PubMedCrossRefGoogle Scholar
- 8.Ding W, Knox TR, Tschumper RC, Wu W, Schwager SM, Boysen JC, Jelinek DF, Kay NE (2010) Platelet-derived growth factor (PDGF)-PDGF receptor interaction activates bone marrow-derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch. Blood 116(16):2984–2993PubMedCrossRefGoogle Scholar
- 9.Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, Mills GB, Ohsaka A, Nagaoka I, Andreeff M, Konopleva M (2007) Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 67(2):684–694PubMedCrossRefGoogle Scholar
- 12.Lis R, Touboul C, Mirshahi P, Ali F, Mathew S, Nolan DJ, Maleki M, Abdalla SA, Raynaud CM, Querleu D, Al-Azwani E, Malek J, Mirshahi M, Rafii A (2010) Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12. Int J Cancer 128(3):715–725CrossRefGoogle Scholar
- 13.Brune JC, Tormin A, Johansson MC, Rissler P, Brosjo O, Lofvenberg R, Vult von Steyern F, Mertens F, Rydholm A, Scheding S (2010) Mesenchymal stromal cells from primary osteosarcoma are non-malignant and strikingly similar to their bone marrow counterparts. Int J Cancer. doi: 10.1002/ijc.25697
- 26.Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348PubMedCrossRefGoogle Scholar
- 27.Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G, Dontu G, Birnbaum D, Wicha MS (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313PubMedCrossRefGoogle Scholar
- 28.Ishizawa K, Rasheed ZA, Karisch R, Wang Q, Kowalski J, Susky E, Pereira K, Karamboulas C, Moghal N, Rajeshkumar NV, Hidalgo M, Tsao M, Ailles L, Waddell TK, Maitra A, Neel BG, Matsui W (2010) Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 7(3):279–282PubMedCrossRefGoogle Scholar
- 30.Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12(5):468–476PubMedCrossRefGoogle Scholar
- 33.Klopp AH, Lacerda L, Gupta A, Debeb BG, Solley T, Li L, Spaeth E, Xu W, Zhang X, Lewis MT, Reuben JM, Krishnamurthy S, Ferrari M, Gaspar R, Buchholz TA, Cristofanilli M, Marini F, Andreeff M, Woodward WA (2010) Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells. PLoS One 5(8):e12180PubMedCrossRefGoogle Scholar