癌症幹細胞 (cancer stem cells, CSCs) 為腫瘤中一群具有腫瘤生成、抗藥性以及促進腫瘤轉移的細胞。研究指出骨髓間質幹細胞 (bone-derived mesenchymal stem cell, BM-MSCs) 在癌症幹細胞利基扮演重要的角色，並能調控癌細胞轉移。此研究發現肺癌細胞中有兩組癌細胞，分別對骨髓間質幹細胞所培養的條件培養液 (MSC-conditioned medium, MSC-CM) 有不同的反應。具上皮細胞型態的LM癌細胞經條件培養液培養後，其STAT3位於Y705的磷酸化有上升的情形，並加強了骨髓間質幹細胞所誘發的上皮-間質轉換 (epithelial-mesenchymal transition, EMT) 及癌症幹性 (cancer stemness)；而在間質型態的HM20癌細胞則觀察到，間質幹細胞所分泌的調控物質增加了HM20中STAT3-S727的磷酸化。STAT3-S727磷酸化同時也強化了由骨髓間質幹細胞所誘發的間質-上皮轉換 (mesenchymal- epithelial transition, MET) 以及癌症幹性的維持。總結上述實驗，此研究發現骨髓間質幹細胞經由STAT3的活化，調控同一細胞株中兩群不同的癌症細胞，以誘發癌症轉移以及維持癌症幹性。

Cancer stem cells (CSCs) are a small subpopulation of cancer cells known to initiate tumor growth, lead to drug resistance and drive tumor metastasis. Studies have shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute to cancer stem cell niche and can regulate cancer metastasis. Our research indicated that two heterogenous subgroups of cancer cells in tumor responsed differently upon MSC-conditional medium (MSC-CM) treatment. MSC-CM elevated STAT3-Y705 phosphorylation in epithelial-type LM cells, and pY705-STAT3 took part in MSC-induced EMT and CSC property induction. STAT3-S727 phosphorylation was enhanced in mesenchymal-type HM20 cells, and contributed to MSC-induced proliferation, MET, and CSC property maintenance. To sum up, we demonstrated that MSCs can induce two-step metastasis cycle on two heterogenous subgroups derived from the same cancer cell line through STAT3-elicited promotion of CSC phenotype.

Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences 100, 3983-3988.
Ankrum, J.A., Ong, J.F., and Karp, J.M. (2014). Mesenchymal stem cells: immune evasive, not immune privileged. Nature Biotechnology 32, 252.
Ansieau, S., Bastid, J., Doreau, A., Morel, A.-P., Bouchet, B.P., Thomas, C., Fauvet, F., Puisieux, I., Doglioni, C., Piccinin, S., et al. (2008). Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence. Cancer Cell 14, 79-89.
Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D., and Rich, J.N. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760.
Barcellos-de-Souza, P., Gori, V., Bambi, F., and Chiarugi, P. (2013). Tumor microenvironment: Bone marrow-mesenchymal stem cells as key players. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1836, 321-335.
Beck, B., and Blanpain, C. (2013). Unravelling cancer stem cell potential. Nature Reviews Cancer 13, 727–738.
Boesch, M., Sopper, S., Zeimet, A.G., Reimer, D., Gastl, G., Ludewig, B., and Wolf, D. (2016). Heterogeneity of Cancer Stem Cells: Rationale for Targeting the Stem Cell Niche. Biochimica et biophysica acta 1866, 276-289.
Boesch, M., Zeimet, A.G., Reimer, D., Schmidt, S., Gastl, G., Parson, W., Spoeck, F., Hatina, J., Wolf, D., and Sopper, S. (2014). The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics. Oncotarget 5, 7027-7039.
Bonnet, D., and Dick, J.E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 3, 730–737.
Brabletz, T. (2012). EMT and MET in Metastasis: Where Are the Cancer Stem Cells? Cancer Cell 22, 699-701.
Brabletz, T., Hlubek, F., Spaderna, S., Schmalhofer, O., Hiendlmeyer, E., Jung, A., and Kirchner, T. (2005). Invasion and Metastasis in Colorectal Cancer: Epithelial-Mesenchymal Transition, Mesenchymal-Epithelial Transition, Stem Cells and β-Catenin. Cells Tissues Organs 179, 56-65.
Bunnell, B.A., Flaat, M., Gagliardi, C., Patel, B., and Ripoll, C. (2008). Adipose-derived stem cells: Isolation, expansion and differentiation. Methods 45, 115-120.
Cabarcas, S.M., Mathews, L.A., and Farrar, W.L. (2011). The cancer stem cell niche—there goes the neighborhood? International Journal of Cancer 129, 2315-2327.
Chaffer, C.L., Brennan, J.P., Slavin, J.L., Blick, T., Thompson, E.W., and Williams, E.D. (2006). Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2. Cancer Research 66, 11271-11278.
Chaffer, C.L., Thompson, E.W., and Williams, E.D. (2007). Mesenchymal to Epithelial Transition in Development and Disease. Cells Tissues Organs 185, 7-19.
Coffelt, S.B., Marini, F.C., Watson, K., Zwezdaryk, K.J., Dembinski, J.L., LaMarca, H.L., Tomchuck, S.L., zu Bentrup, K.H., Danka, E.S., Henkle, S.L., et al. (2009). The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proceedings of the National Academy of Sciences 106, 3806-3811.
Dalerba, P., Dylla, S.J., Park, I.-K., Liu, R., Wang, X., Cho, R.W., Hoey, T., Gurney, A., Huang, E.H., Simeone, D.M., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences 104, 10158-10163.
del Pozo Martin, Y., Park, D., Ramachandran, A., Ombrato, L., Calvo, F., Chakravarty, P., Spencer-Dene, B., Derzsi, S., Hill, Caroline S., Sahai, E., et al. (2015). Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization. Cell Reports 13, 2456-2469.
Dick, J.E. (2008). Stem cell concepts renew cancer research. Blood 112, 4793-4807.
Dontu, G., Abdallah, W.M., Foley, J.M., Jackson, K.W., Clarke, M.F., Kawamura, M.J., and Wicha, M.S. (2003). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes & development 17, 1253-1270.
Fan, F., Samuel, S., Evans, K.W., Lu, J., Xia, L., Zhou, Y., Sceusi, E., Tozzi, F., Ye, X.-C., Mani, S.A., et al. (2012). Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell–like phenotype in human colorectal cancer cells. Cancer Medicine 1, 5-16.
Fessler, E., Dijkgraaf, F.E., De Sousa E Melo, F., and Medema, J.P. (2013). Cancer stem cell dynamics in tumor progression and metastasis: Is the microenvironment to blame? Cancer Letters 341, 97-104.
Frisch, S.M., and Screaton, R.A. (2001). Anoikis mechanisms. Current Opinion in Cell Biology 13, 555-562.
Galoczova, M., Coates, P., and Vojtesek, B. (2018). STAT3, stem cells, cancer stem cells and p63. Cellular & Molecular Biology Letters 23, 12.
Ghoshal, S., Fuchs, B.C., and Tanabe, K.K. (2016). STAT3 is a key transcriptional regulator of cancer stem cell marker CD133 in HCC. Hepatobiliary Surgery and Nutrition 5, 201-203.
Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., Jacquemier, J., Viens, P., Kleer, C.G., Liu, S., et al. (2007). ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell 1, 555-567.
Gregory, C.A., Prockop, D.J., and Spees, J.L. (2005). Non-hematopoietic bone marrow stem cells: Molecular control of expansion and differentiation. Experimental Cell Research 306, 330-335.
Grosse-Gehling, P., Fargeas, C.A., Dittfeld, C., Garbe, Y., Alison, M.R., Corbeil, D., and Kunz-Schughart, L.A. (2013). CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. The Journal of Pathology 229, 355-378.
Hazan-Halevy, I., Harris, D., Liu, Z., Liu, J., Li, P., Chen, X., Shanker, S., Ferrajoli, A., Keating, M.J., and Estrov, Z. (2010). STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 115, 2852-2863.
Hemmati, H.D., Nakano, I., Lazareff, J.A., Masterman-Smith, M., Geschwind, D.H., Bronner-Fraser, M., and Kornblum, H.I. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences 100, 15178-15183.
Hodge, D.R., Hurt, E.M., and Farrar, W.L. (2005). The role of IL-6 and STAT3 in inflammation and cancer. European Journal of Cancer 41, 2502-2512.
Jing, Y., Han, Z., Liu, Y., Sun, K., Zhang, S., Jiang, G., Li, R., Gao, L., Zhao, X., Wu, D., et al. (2012). Mesenchymal Stem Cells in Inflammation Microenvironment Accelerates Hepatocellular Carcinoma Metastasis by Inducing Epithelial-Mesenchymal Transition. PLOS ONE 7, e43272.
Johnson, D.E., O'Keefe, R.A., and Grandis, J.R. (2018). Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature Reviews Clinical Oncology 15, 234-248.
Kalluri, R., and Weinberg, R.A. (2009). The basics of epithelial-mesenchymal transition. The Journal of Clinical Investigation 119, 1420-1428.
Karnoub, A.E., Dash, A.B., Vo, A.P., Sullivan, A., Brooks, M.W., Bell, G.W., Richardson, A.L., Polyak, K., Tubo, R., and Weinberg, R.A. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557-563.
Lamouille, S., Xu, J., and Derynck, R. (2014). Molecular mechanisms of epithelial–mesenchymal transition. Nature Reviews Molecular Cell Biology 15, 178-196.
Lin, L., Fuchs, J., Li, C., Olson, V., Bekaii-Saab, T., and Lin, J. (2011). STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH(+)/CD133(+) stem cell-like human colon cancer cells. Biochemical and biophysical research communications 416, 246-251.
Liu, C.-C., Lin, S.-P., Hsu, H.-S., Yang, S.-H., Lin, C.-H., Yang, M.-H., Hung, M.-C., and Hung, S.-C. (2016). Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells. Nature Communications 7, 11798.
Liu, S., Cong, Y., Wang, D., Sun, Y., Deng, L., Liu, Y., Martin-Trevino, R., Shang, L., McDermott, Sean P., Landis, Melissa D., et al. (2014). Breast Cancer Stem Cells Transition between Epithelial and Mesenchymal States Reflective of their Normal Counterparts. Stem Cell Reports 2, 78-91.
Mani, S.A., Guo, W., Liao, M.-J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F., Zhang, C.C., Shipitsin, M., et al. (2008). The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell 133, 704-715.
Marotta, L.L.C., Almendro, V., Marusyk, A., Shipitsin, M., Schemme, J., Walker, S.R., Bloushtain-Qimron, N., Kim, J.J., Choudhury, S.A., Maruyama, R., et al. (2011). The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24– stem cell–like breast cancer cells in human tumors. The Journal of Clinical Investigation 121, 2723-2735.
Martin, F.T., Dwyer, R.M., Kelly, J., Khan, S., Murphy, J.M., Curran, C., Miller, N., Hennessy, E., Dockery, P., Barry, F.P., et al. (2010). Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Research and Treatment 124, 317-326.
Miyoshi, A., Kitajima, Y., Kido, S., Shimonishi, T., Matsuyama, S., Kitahara, K., and Miyazaki, K. (2005). Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. British Journal Of Cancer 92, 252-258.
Patrawala, L., Calhoun, T., Schneider-Broussard, R., Zhou, J., Claypool, K., and Tang, D.G. (2005). Side Population Is Enriched in Tumorigenic, Stem-Like Cancer Cells, whereas ABCG2⁺ and ABCG2⁻ Cancer Cells Are Similarly Tumorigenic. Cancer Research 65, 6207-6219.
Plaks, V., Kong, N., and Werb, Z. (2015). The Cancer Stem Cell Niche: How Essential Is the Niche in Regulating Stemness of Tumor Cells? Cell Stem Cell 16, 225-238.
Polyak, K., and Weinberg, R.A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Reviews Cancer 9, 265-273.
Prince, M.E., Sivanandan, R., Kaczorowski, A., Wolf, G.T., Kaplan, M.J., Dalerba, P., Weissman, I.L., Clarke, M.F., and Ailles, L.E. (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proceedings of the National Academy of Sciences 104, 973-978.
Qin, H.R., Kim, H.-J., Kim, J.-Y., Hurt, E.M., Klarmann, G.J., Kawasaki, B.T., Serrat, M.A.D., and Farrar, W.L. (2008). Activation of Stat3 through a Phosphomimetic Serine727 Promotes Prostate Tumorigenesis Independent of Tyrosine705 phosphorylation. Cancer research 68, 7736-7741.
Schäfer, M., and Werner, S. (2008). Cancer as an overhealing wound: an old hypothesis revisited. Nature Reviews Molecular Cell Biology 9, 628-638.
Schroeder, A., Herrmann, A., Cherryholmes, G., Kowolik, C., Buettner, R., Pal, S., Yu, H., Muller-Newen, G., and Jove, R. (2014). Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res 74, 1227-1237.
Shackleton, M., Quintana, E., Fearon, E.R., and Morrison, S.J. (2009). Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution. Cell 138, 822-829.
Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., and Dirks, P.B. (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.
Smith, B., and Bhowmick, N. (2016). Role of EMT in Metastasis and Therapy Resistance. Journal of Clinical Medicine 5, 17.
Takaishi, M., Tarutani, M., Takeda, J., and Sano, S. (2016). Mesenchymal to Epithelial Transition Induced by Reprogramming Factors Attenuates the Malignancy of Cancer Cells. PLoS ONE 11, e0156904.
Thiery, J.P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature Reviews Cancer 2, 442-454.
Thiery, J.P., Acloque, H., Huang, R.Y.J., and Nieto, M.A. (2009). Epithelial-Mesenchymal Transitions in Development and Disease. Cell 139, 871-890.
Todaro, M., Alea, M.P., Di Stefano, A.B., Cammareri, P., Vermeulen, L., Iovino, F., Tripodo, C., Russo, A., Gulotta, G., Medema, J.P., et al. (2007). Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4. Cell Stem Cell 1, 389-402.
Tu, B., Du, L., Fan, Q.-M., Tang, Z., and Tang, T.-T. (2012). STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Letters 325, 80-88.
Tu, B., Zhu, J., Liu, S., Wang, L., Fan, Q., Hao, Y., Fan, C., and Tang, T.-T. (2016). Mesenchymal stem cells promote osteosarcoma cell survival and drug resistance through activation of STAT3. Oncotarget 7, 48296-48308.
Valent, P., Bonnet, D., De Maria, R., Lapidot, T., Copland, M., Melo, J.V., Chomienne, C., Ishikawa, F., Schuringa, J.J., Stassi, G., et al. (2012). Cancer stem cell definitions and terminology: the devil is in the details. Nature Reviews Cancer 12, 767-775.
Visvader, J.E., and Lindeman, G.J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Reviews Cancer 8, 755-768.
Wang, M.-L., Pan, C.-M., Chiou, S.-H., Chen, W.-H., Chang, H.-Y., Lee, O.K.-S., Hsu, H.-S., and Wu, C.-W. (2012). Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect. Cancer Research 72, 6051-6064.
Wen, Z., Zhong, Z., and Darnell, J.E., Jr. (1995). Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241-250.
Wright, M.H., Calcagno, A.M., Salcido, C.D., Carlson, M.D., Ambudkar, S.V., and Varticovski, L. (2008). Brca1 breast tumors contain distinct CD44+/CD24- and CD133+cells with cancer stem cell characteristics. Breast Cancer Research 10, R10.
Wu, C., Wei, Q., Utomo, V., Nadesan, P., Whetstone, H., Kandel, R., Wunder, J.S., and Alman, B.A. (2007). Side Population Cells Isolated from Mesenchymal Neoplasms Have Tumor Initiating Potential. Cancer Research 67, 8216-8222.
Xue, Z., Wu, X., Chen, X., Liu, Y., Wang, X., Wu, K., Nie, Y., and Fan, D. (2015). Mesenchymal Stem Cells Promote Epithelial to Mesenchymal Transition and Metastasis in Gastric Cancer Though Paracrine Cues and Close Physical Contact. Journal of Cellular Biochemistry 116, 618-627.
Yang, J., Mani, S.A., Donaher, J.L., Ramaswamy, S., Itzykson, R.A., Come, C., Savagner, P., Gitelman, I., Richardson, A., and Weinberg, R.A. (2004). Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell 117, 927-939.
Yang, J., and Weinberg, R.A. (2008). Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Developmental Cell 14, 818-829.
Yao, D., Dai, C., and Peng, S. (2011). Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation. Molecular Cancer Research 9, 1608-1620.
Yu, H., Lee, H., Herrmann, A., Buettner, R., and Jove, R. (2014). Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature Reviews Cancer 14, 736-746.
Yuan, Z.-l., Guan, Y.-j., Chatterjee, D., and Chin, Y.E. (2005). Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue. Science 307, 269-273.
Zhang, X., Blenis, J., Li, H.C., Schindler, C., and Chen-Kiang, S. (1995). Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 267, 1990-1994.