Focus on sarcomas.
Explore the source record for details and available documents.
Cell Differentiation↗
Biomedical subjects
Lee J Helman
Publications and source records attributed to Lee J Helman.
Seven BMPs and all their receptors are simultaneously expressed in osteosarcoma cells.
Members of the bone morphogenetic protein (BMP) family and their receptors (BMPRs and activin receptors-ActRs) promote the development of bones with a fine regulation of their expression. Mutations in BMPs or BMPRs cause several diseases, as shown in knockout mice, such as skeletal defects, familial primary pulmonary hypertension and neoplasias. Osteosarcoma is the most frequent primary malignant tumor of bone. Due to their importance in bone development, BMPs, BMPRs and ActRs could also play a role in osteosarcoma growth and development. Previous data have shown that the overexpression of the BMPR-II was related to poor prognosis in malignant and metastatic bone tumors. We evaluate by reverse transcription-linked polymerase chain reaction analysis (RT-PCR) the expression pattern of BMPs, BMPRs and ActRs in five different human osteosarcoma cell lines (MG63, G292, HOS, SaOS and U2). Moreover, we performed the mutational screening of the complete BMPR-II mRNA by automated sequencing of the correspondent cDNA to evaluate the presence of point mutations in osteosarcoma cell lines. All the osteosarcoma cell lines studied simultaneously expressed the BMPs, BMPRs and ActRs investigated. No mutations were detected in the BMPR-II cDNA. Our results suggest the presence of a mechanism involving the simultaneous activation of the BMPs and their receptors in osteosarcoma cell lines.
Activin Receptors↗
A randomized controlled trial of octreotide pamoate long-acting release and carboplatin versus carboplatin alone in dogs with naturally occurring osteosarcoma: evaluation of insulin-like growth factor suppression and chemotherapy.
PURPOSE: The purpose of this research was to determine whether insulin-like growth factor (IGF) suppression, using a long-acting analogue of somatostatin (OncoLAR, octreotide pamoate long-acting release), will decrease chemotherapy resistance by eliminating an important survival signal to osteosarcoma (OSA) cells in a relevant naturally occurring cancer model. EXPERIMNETAL DESIGN: We conducted a randomized, blinded, placebo-controlled preclinical study in pet dogs with naturally occurring OSA. The study compared primary tumor necrosis and apoptosis, and survival of pet dogs receiving OncoLAR and carboplatin chemotherapy compared with dogs receiving placebo and carboplatin. RESULTS: Dogs receiving OncoLAR had suppression of serum IGF levels by approximately 43% without toxicity. No differences in primary tumor necrosis, apoptosis, tumor IGF mRNA expression, or survival were seen between the dogs receiving OncoLAR plus chemotherapy compared with OncoLAR alone. CONCLUSION: The suppression of IGF levels by the extent and/or duration achieved in the trial was not sufficient to improve chemotherapy-related antitumor effects in pet dogs with OSA.
Animals↗
Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway.
Insulin-like growth factor (IGF-II) is overexpressed in a variety of human tumors and has both mitogenic and antiapoptotic activity. Although the mechanisms of IGF-II-induced proliferation have been well studied, the mechanisms underlying its survival signaling have been less well characterized. In this report, we investigated the role of IGF-II on cisplatin-induced apoptosis. We found that IGF-II overexpression was associated with an increase in p70 ribosomal protein S6 kinase (p70 S6K). Cisplatin treatment of C2C12 mouse myoblasts led to cell death associated with an inhibition of p70 S6K activity. Endogenous or exogenous IGF-II addition to C2C12 cells caused protection to cisplatin-induced apoptosis. This protection was associated in both cases with an increase in p70 S6K basal activity as well as resistance to cisplatin-induced decreased activity. Blockade of p70 S6K activation by rapamycin abrogated the IGF-II-mediated protection of cells to cisplatin-induced apoptosis. Furthermore, treatment of IGF-II-overexpressing Rh30 and CTR rhabdomyosarcoma cells with rapamycin restored sensitivity to cisplatin-induced apoptosis. These data together suggest that IGF-II-associated protection to cisplatin-induced apoptosis is mediated through an activation of the p70 S6K pathway. Thus, inhibition of the p70 S6 pathway may enhance chemotherapy-induced apoptosis in the treatment of IGF-II-overexpressing tumors.
Adaptor Proteins, Signal Transducing↗
Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulin-like growth factor-1 serum levels.
BACKGROUND: Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies. STUDY PURPOSE: To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS. DESIGN/METHODS: A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily. RESULTS: There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% ( < 0.0001, n = 21) and 53% ( = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (DeltaAUC) for arginine-stimulated GH serum levels at week two was lower than baseline ( < 0.01). At weeks two and eight, GH peak values were lower than baseline ( < 0.0001 and = 0.002, respectively). CONCLUSIONS: A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.
Adolescent↗
The biology of metastases in pediatric sarcomas.
In the treatment of pediatric solid tumors, the presence or development of metastatic disease carries a universally poor prognosis. In fact, most cancer deaths result from metastases rather than primary tumor growth. Although the poor outcome associated with metastatic disease has been known for some time, an understanding of the processes that allow a cancer to disseminate is only now beginning to be understood. In order for a cancer to spread beyond its local site, a complex series of events must be undertaken that must allow the cancer not only to travel into and through the circulation but also prevent elimination of these cells by the host, as well as promote growth at the metastatic site. This review presents a current model of these processes. Some of the key molecular factors influencing their development are outlined in the context of this model. We present recent advances in our understanding of metastases, especially as they relate to experimental therapies and possible molecular targets of future therapies. Finally, we discuss progress being made in our ability to study metastases and expectations for the future.
Humans↗
Tumor expression of 4-1BB ligand sustains tumor lytic T cells.
Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28-/4-1BB+. Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer.
4-1BB Ligand↗