Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

Abstract

BackgroundOsteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated.MethodsStudies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. ResultsFunctional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development.ConclusionsWhile future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2909-6) contains supplementary material, which is available to authorized users.

Carboxypeptidase A4 promotes migration and invasion of lung cancer cells, and is closely associated with lymph node metastasis

“…IHC scoring showed that CPA4 staining also gradually enhanced, suggesting that CPA4 plays essential roles in lymph node metastasis of lung cancer. It has been reported that secreted proteases participate in the degradation and remodeling of extracellular matrix, regulate the tumor microenvironment, and promote the invasion and metastasis of tumor cells . As a secreted protein, CPA4 might be released from the primary lung cancer tissues to serum to establish a tumor microenvironment for metastasis.…”

“…It has been reported that secreted proteases participate in the degradation and remodeling of extracellular matrix, regulate the tumor microenvironment, and promote the invasion and metastasis of tumor cells. 16,17 As a secreted protein, CPA4 might be released from the primary lung cancer tissues to serum to establish a tumor microenvironment for metastasis. In the future, we will detect the serum levels of CPA4 for validating the efficacy of CPA4 for early detection of lung cancer lymph node metastasis.…”

Three‐Dimensional Osteosarcoma Models for Advancing Drug Discovery and Development

“…Matrigel Hydrogel HOS, 143B -pLKO.1 shsFRP2 vector [73] 143B, MG-63, U2OS, hFOB1.19 -Paris polyphylla ethanol extract [75] MG-63 -miR-29b-1 overexpression [76] K7M2 -Bromodomain inhibitor JQ1 [77] Collagen Hydrogel U2OS -Kinase inhibitor PI103 [43] Type I MG-63 -Tyrosin phosphorylation inhibitor (ACM-14) [91] LM8 -Pazopanib [96] Sponge hFOB 1.19 (osteoblasts) PC3, LNCaP siRNA-based gene knockdown [97] Matrigel/Collagen Hydrogel MOS, U2OS, 143B, ZK58, KPD, SaOS-2 Trametinib, AZD8330, and TAK-733 kinase inhibitors [79] MOS, U2OS, 143B, ZK58, KPD -siAven [78] Silk Fibroin Sponge 143.98.2, SaOS-2, U2OS -Doxorubicin, cisplatin [108] U2OS Bone marrow fibroblasts, HUVECs MAB208 (anti-IL-8), Avastin (anti-VEGF-A) [109] MG-63 MDA-MB-231 Doxorubicin [110] MG-63 MDA-MB-231, MSCs Paclitaxel [111] Chitosan Sponge MG-63, MNNG -Doxorubicin [139] Alginate Hydrogel MG-63 -Tetracycline hydrochloride [115] Fibers MG-63 HUVECs - [116] Spheres Dunn, LM8 NF-кB decoy oligodeoxy-nucleotide [124] Synthetic Biomaterials…”

“…[73] sFRP2 is involved in Wingless signaling pathway and its overexpression has been associated with metastatic ability of cancer cells. [73] Yao et al also proposed an antimetastatic therapy based on Paris polyphylla ethanol extract, which demonstrated to suppress cell proliferation and inhibit cell migration, invasion, and vasculogenic mimicry formation, in both 3D Matrigel in vitro model and in a xenograft model. [73] Yao et al also proposed an antimetastatic therapy based on Paris polyphylla ethanol extract, which demonstrated to suppress cell proliferation and inhibit cell migration, invasion, and vasculogenic mimicry formation, in both 3D Matrigel in vitro model and in a xenograft model.…”

Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis

“…The preponderance of in vivo evidence supports that SFRP2 stimulates tumor growth. Gain of function studies have shown that SFRP2 strongly promotes tumor growth of intracranial glioma [1], renal cell carcinoma [2], lung cancer [3], melanoma [4], and osteosarcoma [5]. Overexpression of transfected SFRP2 in MCF7 breast adenocarcinoma cells increased their resistance to apoptotic signals in vitro [6].…”