Endosialin Protein Expression and Therapeutic Target Potential in Human Solid Tumors: Sarcoma versus Carcinoma

Rouleau, Cecile; Curiel, Maritza; Weber, William; Smale, Robert; Kurtzberg, Leslie; Mascarello, James T.; Berger, Carol S.; Wallar, Gina; Bagley, Rebecca G.; Honma, Nakayuki; Hasegawa, Koki; Ishida, Isao; Kataoka, Satoshi; Thurberg, Beth L.; Mehraein, Khodadad; Horten, Bruce; Miller, Glenn A.; Teicher, Beverly A.

doi:10.1158/1078-0432.ccr-08-0499

Cited by 90 publications

(124 citation statements)

References 30 publications

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“…The A673 cell line was described in 1973 as being from a patient with a possible rhabdomyosarcoma; however, recent cytogenetic testing and molecular profiling established that A673 cells express the EWS/FLI1 transcription factor and confirmed that A673 cells are Ewing sarcoma (Figure 1). 17–19 A673 cells grown as a human tumor xenograft in immunodeficient mice have proven to be a useful in vivo model to explore the biology of tumor growth and to identify therapeutic targets for sarcomas.…”

Section: Ewing/pnet Sarcoma Model Systemsmentioning

confidence: 99%

“…In 2005, Dolznig et al showed expression of endosialin transcript in sarcomas, and expression of the protein in malignant cells in one malignant fibrous histiocytoma and one liposarcoma 53. More recently, endosialin protein expression was assessed by immunohistochemistry in 250 clinical specimens of human cancer, including 20 cancer subtypes 19. The results showed that endosialin protein is frequently found in human cancers.…”

Section: Sarcoma Targetsmentioning

confidence: 99%

“…Fifty human tumor cell lines and six normal cell types in culture were assayed by RT-PCR and/or flow cytometry for endosialin 19. Endosialin cell surface protein was found on 7 sarcoma lines, 1 neuroblastoma and 4 normal cell types in culture.…”

Section: Sarcoma Targetsmentioning

confidence: 99%

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Characteristics of human Ewing/PNET sarcoma models

Teicher¹,

Rouleau²,

Kruger³

et al. 2011

Annals of Saudi Medicine

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Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available.

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Section: Ewing/pnet Sarcoma Model Systemsmentioning

confidence: 99%

Section: Sarcoma Targetsmentioning

confidence: 99%

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Characteristics of human Ewing/PNET sarcoma models

Teicher¹,

Rouleau²,

Kruger³

et al. 2011

Annals of Saudi Medicine

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“…Endosialin/CD248/TEM1, a transmembrane glycoprotein expressed on pericytes and fibroblasts during tissue development and present in the adult in several mesenchymal cell types, is associated with tumor neovascularization and inflammation and has emerged as a molecular marker and therapeutic target for sarcoma (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). First recognized as the antigen of an antibody raised in mice against human fetal fibroblasts (FB5), endosialin was found to be expressed by human solid tumor vasculature (13) and was detected in a subset of cells enriched for endothelium via selection with P1H12, an anti-CD146 antibody, from a colorectal tumor specimen (14).…”

Section: Introductionmentioning

confidence: 99%

“…Staining intensity was scored on the scale 0, 1þ, 2þ, 3þ. All nine sarcoma subtypes tested included specimens with at least 50% immunoreactive tissue components positive with a minimum of 2þ staining intensity, indicating the high prevalence of endosialin in sarcomas (12). A retrospective analysis of diagnostic reports showed that endosialin can be detected in high-grade disease and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Anti-Endosialin Antibody–Drug Conjugate: Potential in Sarcoma and Other Malignancies

Rouleau¹,

Gianolio²,

Smale³

et al. 2015

Molecular Cancer Therapeutics

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Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-positive cells in vitro and achieved profound and durable antitumor efficacy in preclinical human tumor xenograft models of endosialin-positive disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE molecules per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the antiendosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors.

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CD248 and its cytoplasmic domain: A therapeutic target for arthritis

Maia¹,

Vriese²,

Janssens³

et al. 2010

Arthritis & Rheumatism

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Objective. CD248 is a transmembrane glycoprotein expressed on the surface of activated perivascular and fibroblast-like cells. This study was undertaken to explore the function of CD248 and its cytoplasmic domain in arthritis.Methods. Synovial tissue biopsy samples from healthy controls, from patients with psoriatic arthritis (PsA), and from patients with rheumatoid arthritis (RA) were stained for CD248. Transgenic mice that were CD248-deficient (CD248-knockout [CD248 KO/KO ]) or mice with CD248 lacking the cytoplasmic domain (CD248 CyD/CyD ) were generated. Collagen antibodyinduced arthritis (CAIA) was induced in these mice and in corresponding wild-type (WT) mice as controls. Clinical signs and histologic features of arthritis were evaluated. Cytokine levels were determined by enzymelinked immunosorbent assay, and the number of infiltrating inflammatory cells was quantified by immunohistochemistry. In vitro studies were performed with fibroblasts from CD248-transgenic mouse embryos to explain the observed effects on inflammation.Results. Immunostaining of synovium from patients with PsA and patients with RA and that from mice after the induction of CAIA revealed strong CD248 expression in perivascular and fibroblast-like stromal cells. CD248 KO/KO and CD248 CyD/CyD mice had less severe arthritis, with lower plasma levels of proinflammatory cytokines, as compared with WT controls. Moreover, the joints of these mice had less synovial hyperplasia, reduced accumulation of inflammatory cells, and less articular cartilage and bone damage. Tumor necrosis factor ␣-induced monocyte adhesion to CD248 CyD/CyD fibroblasts was impaired. CD248 CyD/CyD fibroblasts exhibited reduced expression of hypoxia-inducible factor 1␣, placental growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9 activity in response to transforming growth factor ␤.Conclusion. CD248 contributes to synovial hyperplasia and leukocyte accumulation in inflammatory arthritis, the effects of which are mediated partly via its cytoplasmic domain. CD248 is therefore a potential new target in the treatment of arthritis.

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Endosialin Protein Expression and Therapeutic Target Potential in Human Solid Tumors: Sarcoma versus Carcinoma

Cited by 90 publications

References 30 publications

Characteristics of human Ewing/PNET sarcoma models

Characteristics of human Ewing/PNET sarcoma models

Anti-Endosialin Antibody–Drug Conjugate: Potential in Sarcoma and Other Malignancies

CD248 and its cytoplasmic domain: A therapeutic target for arthritis

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