ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone

Nicholas Greco, Trevor Schott, Xiaodong Mu, Adam Rothenberg, Clifford Voigt, Richard L. McGough III, Mark Goodman, Johnny Huard, Kurt R. Weiss

Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA.

DOI: 10.4236/jct.2014.54040                

Abstract

Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor’s cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further.

Keywords

Osteosarcoma, Chondrosarcoma, Ewings Sarcoma, Aldehyde Dehydrogenase, Metastases

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Dai, X., Ma, W., He, X. and Jha, R.K. (2011) Review of Therapeutic Strategies for Osteosarcoma, Chondrosarcoma, and Ewing’s Sarcoma. Medical Science Monitor, 17, RA177. http://dx.doi.org/10.12659/MSM.881893
[2]	Damron, T.A., Ward, W.G. and Stewart, A. (2007) Osteosarcoma, Chondrosarcoma, and Ewing’s Sarcoma: National Cancer Data Base Report. Clinical Orthopaedics and Related Research, 459, 40-47. http://dx.doi.org/10.1097/BLO.0b013e318059b8c9
[3]	Hameed, M. and Dorfman, H. (2011) Primary Malignant Bone Tumors—Recent Developments. Seminars in Diagnostic Pathology, 28, 86-101. http://dx.doi.org/10.1053/j.semdp.2011.02.002
[4]	Qureshi, A., Ahmad, Z., Azam, M. and Idrees, R. (2010) Epidemiological Data for Common Bone Sarcomas. Asian Pacific Journal of Cancer Prevention, 11, 393-395.
[5]	Skubitz, K.M. and D’Adamo, D.R. (2007) Sarcoma. Mayo Clinic Proceedings, 82, 1409-1432. http://dx.doi.org/10.4065/82.11.1409
[6]	Whelan, J., McTiernan, A., Cooper, N., Wong, Y.K., Francis, M., Vernon, S., et al. (2012) Incidence and Survival of Malignant Bone Sarcomas in England 1979-2007. International Journal of Cancer, 131, E508-E517. http://dx.doi.org/10.1002/ijc.26426
[7]	Brage, M.E. and Simon, M.A. (1992) Evaluation, Prognosis, and Medical Treatment Considerations of Metastatic Bone Tumors. Orthopedics, 15, 589-596.
[8]	Riccio, A.I., Wodajo, F.M. and Malawer, M. (2007) Metastatic Carcinoma of the Long Bones. American Family Physician, 76, 1489-1494.
[9]	Chmielowski, B., Federman, N. and Tap, W.D. (2012) Clinical Trial End Points for Assessing Efficacy of Novel Therapies for Soft-Tissue Sarcomas. Expert Review of Anticancer Therapy, 12, 1217-1228. http://dx.doi.org/10.1586/era.12.100
[10]	Kondo, T., Suehara, Y., Kikuta, K., Kubota, D., Tajima, T., Mukaihara, K., et al. (2013) Proteomic Approach toward Personalized Sarcoma Treatment: Lessons from Prognostic Biomarker Discovery in Gastrointestinal Stromal Tumor. Proteomics—Clinical Applications, 7, 70-78. http://dx.doi.org/10.1002/prca.201200085
[11]	Schoffski, P. (2012) Pazopanib in the Treatment of Soft Tissue Sarcoma. Expert Review of Anticancer Therapy, 12, 711-723. http://dx.doi.org/10.1586/era.12.41
[12]	Sinha, S. and Peach, A.H. (2010) Diagnosis and Management of Soft Tissue Sarcoma. BMJ, 341, c7170. http://dx.doi.org/10.1136/bmj.c7170
[13]	Guma, S.R., Lee, D.A., Yu, L., Gordon, N., Hughes, D., Stewart, J., et al. (2014) Natural Killer Cell Therapy and Aerosol Interleukin-2 for the Treatment of Osteosarcoma Lung Metastasis. Pediatric Blood & Cancer, 61, 618-626. http://dx.doi.org/10.1002/pbc.24801
[14]	Heck Jr., R.K., Peabody, T.D. and Simon, M.A. (2006) Staging of Primary Malignancies of Bone. CA: A Cancer Journal for Clinicians, 56, 366-375. http://dx.doi.org/10.3322/canjclin.56.6.366
[15]	Mu, X., Isaac, C., Greco, N., Huard, J. and Weiss, K. (2013) Notch Signaling Is Associated with ALDH Activity and an Aggressive Metastatic Phenotype in Murine Osteosarcoma Cells. Frontiers in Oncology, 3, 143. http://dx.doi.org/10.3389/fonc.2013.00143
[16]	Mu, X., Isaac, C., Schott, T., Huard, J. and Weiss, K. (2013) Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells. Sarcoma, 2013, 480713. http://dx.doi.org/10.1155/2013/480713
[17]	Mu, X., Sultankulov, B., Agarwal, R., Mahjoub, A., Schott, T., Greco, N., et al. (2013) Chick Embryo Extract Demethylates Tumor Suppressor Genes in Osteosarcoma Cells. Clinical Orthopaedics and Related Research, 472, 865-873. http://dx.doi.org/10.1007/s11999-013-3104-6
[18]	Riad, S., Griffin, A.M., Liberman, B., Blackstein, M.E., Catton, C.N., Kandel, R.A., et al. (2004) Lymph Node Metastasis in Soft Tissue Sarcoma in an Extremity. Clinical Orthopaedics and Related Research, 426, 129-134. http://dx.doi.org/10.1097/01.blo.0000141660.05125.46
[19]	Herget, G.W., Uhl, M., Opitz, O.G., Adler, C.P., Sudkamp, N.P. and Knoller, S. (2011) The Many Faces of Chondrosarcoma of Bone, Own Cases and Review of the Literature with an Emphasis on Radiology, Pathology and Treatment. Acta chirurgiae orthopaedicae et traumatologiae Cechoslovaca, 78, 501-509.
[20]	Mavrogenis, A.F., Ruggieri, P., Mercuri, M. and Papagelopoulos, P.J. (2011) Dedifferentiated Chondrosarcoma Revisited. Journal of Surgical Orthopaedic Advances, 20, 106-111.
[21]	Gordon, N. and Kleinerman, E.S. (2010) Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 23, 189-196. http://dx.doi.org/10.1089/jamp.2009. 0812
[22]	Weiss, K.R., Cooper, G.M., Jadlowiec, J.A., McGough III, R.L. and Huard, J. (2006) VEGF and BMP Expression in Mouse Osteosarcoma Cells. Clinical Orthopaedics and Related Research, 450, 111-117. http://dx.doi.org/10.1097/01.blo.0000229333.98781.56
[23]	Bortolomai, I., Canevari, S., Facetti, I., De Cecco, L., Castellano, G., Zacchetti, A., et al. (2010) Tumor Initiating Cells: Development and Critical Characterization of a Model Derived from the A431 Carcinoma Cell Line Forming Spheres in Suspension. Cell Cycle, 9, 1194-1206. http://dx.doi.org/10.4161/cc.9.6.11108
[24]	Burger, P.E., Gupta, R., Xiong, X., Ontiveros, C.S., Salm, S.N., Moscatelli, D., et al. (2009) High Aldehyde Dehydrogenase Activity: A Novel Functional Marker of Murine Prostate Stem/Progenitor Cells. Stem Cells, 27, 2220-2228. http://dx.doi.org/10.1002/stem.135
[25]	Charafe-Jauffret, E., Ginestier, C., Iovino, F., Tarpin, C., Diebel, M., Esterni, B., et al. (2010) Aldehyde Dehydrogenase 1-Positive Cancer Stem Cells Mediate Metastasis and Poor Clinical Outcome in Inflammatory Breast Cancer. Clinical Cancer Research, 16, 45-55. http://dx.doi.org/10.1158/1078-0432.CCR-09-1630
[26]	Clay, M.R., Tabor, M., Owen, J.H., Carey, T.E., Bradford, C.R., Wolf, G.T., et al. (2010) Single-Marker Identification of Head and Neck Squamous Cell Carcinoma Cancer Stem Cells with Aldehyde Dehydrogenase. Head Neck, 32, 1195-1201. http://dx.doi.org/10.1002/hed.21315
[27]	Croker, A.K., Goodale, D., Chu, J., Postenka, C., Hedley, B.D., Hess, D.A., et al. (2009) High Aldehyde Dehydrogenase and Expression of Cancer Stem Cell Markers Selects for Breast Cancer Cells with Enhanced Malignant and Metastatic Ability. Journal of Cellular and Molecular Medicine, 13, 2236-2252. http://dx.doi.org/10.1111/j.1582-4934.2008.00455.x
[28]	Deng, S., Yang, X., Lassus, H., Liang, S., Kaur, S., Ye, Q., et al. (2010) Distinct Expression Levels and Patterns of Stem Cell Marker, Aldehyde Dehydrogenase Isoform 1 (ALDH1), in Human Epithelial Cancers. PLoS One, 5, e10277. http://dx.doi.org/10.1371/journal.pone.0010277
[29]	Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., 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. http://dx.doi.org/10.1016/j.stem.2007.08.014