Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma

BACKGROUND: Osteosarcoma is a very aggressive tumor with a propensity to metastasize and invade surrounding tissue. Identification of the molecular determinants of invasion and metastatic potential may guide the development of a rational strategy for devising specific therapies that target the pathways leading to osteosarcoma. METHODS: In this study, we used pathway-focused low density expression cDNA arrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on osteosarcoma patient tumor samples and correlated with clinical and pathological data. RESULTS: THBS3, SPARC and SPP1 were identified as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p = 0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51/55 (96.3%) osteosarcoma samples derived from 43 patients, and correlated with the worst event-free survival (p = 0.03) and relapse free survival (p = 0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis. CONCLUSION: In this study three genes were identified with pattern of differential gene expression associated with a phenotypic role in metastasis and invasion. Interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker

Insights on PRAME and osteosarcoma by means of gene expression profiling

Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers. The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology. We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles. PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis. The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.FAPESP (The State of Sao Paulo Research Foundation)[04/12150-8]FAPESP (The State of Sao Paulo Research Foundation)[07/53869-3]GRAACC (Grupo de Apoio ao Adolescente e Crianca com Cancer

Insights on PRAME and osteosarcoma by means of gene expression profiling

Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers.The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology.We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles.PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis.The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)GRAACC (Grupo de Apoio ao Adolescente e Crianca com Cancer)Universidade Federal de São Paulo, UNIFESP, Pediat Oncol Inst GRAACC, Dept Pediat,Genet Lab, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023062 São Paulo, BrazilUniv São Paulo, Dept Clin Med, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Fac Med Ribeirao Preto, Ctr Cellbased Therapy, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Dept Genet & Evolutionary Biol, BR-14049 Ribeirao Preto, SP, BrazilAlbert Einstein Res & Educ Inst, São Paulo, BrazilUniv São Paulo, Dept Genet, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Dept Pediat, BR-14049 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped Surg & Traumatol, BR-04023062 São Paulo, BrazilLudwig Inst, New York, NY USAUniversidade Federal de São Paulo, UNIFESP, Pediat Oncol Inst GRAACC, Dept Pediat,Genet Lab, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped Surg & Traumatol, BR-04023062 São Paulo, BrazilFAPESP: 04/12150-8FAPESP: 07/53869-3Web of Scienc