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Abstract

INTRODUCTION AND OBJECTIVE: Synovial sarcoma (SS) is a high-grade malignant tumor of mesenchymal origin, accounting for approximately 5-10% of cases of all soft tissue sarcomas (STS). Unlike the majority of STS, SS can occur at any age, with prevalence in adolescents and young adults aged 15 to 40 years and in virtually all anatomical sites of the body, occurring predominantly in the extremities. Despite all the recent advances in knowledge about tumor biology and a more defined role for chemotherapy and radiotherapy, the outcomes for SS patients have not changed significantly. The rarity, histological diversity, propensity to metastases and variations in responses to systemic therapies emphasize the need to develop new therapeutic strategies for SS. Unlike cell line xenografts, the patient-derived xenograft (PDX) model is able to preserve the gene expression, mutational status, histologic architecture, microenvironment composition and heterogeneity of the patient’s tumor. However, few studies on the PDX model of SS were developed so far. Our goal was to establish and characterize the PDX model of SS in immunodeficient mice. MATERIAL AND METHOD: All procedures were approved by the Research Ethics Committees (human and animal) of the institution. Fresh tumor samples were obtained from diagnostic biopsy, amputation or resection surgeries, minced into fragments of approximately 5 mm³ and implanted into the subcutaneous flank of nude mice (P0 generation). After reaching the 200 mm³ threshold (onset of tumor growth), the tumor was measured weekly until reaching 1500-2000 mm³. Then, the mice were euthanized, the tumors resected, fragmented and re-transplanted into new hosts, until the establishment of 3 PDX generations of each patient. Tumor samples (patients and PDX) were fixed with 4% buffered formaldehyde and processed for histological analysis. RESULTS AND CONCLUSION: Samples of 8 patients (4 male and 4 female) with diagnosis of SS were implanted into nude mice. Most tumors (7) were located in the lower limb and the median age of the patients was 39 years (range, 6-60). The source of the sample was biopsy (3), amputation (3) or resection (2). Moreover, 5 samples represented the monophasic subtype and 1 sample the biphasic. However, the subtype of 2 samples, obtained by biopsy, could not be determined. Seven SS samples (87.5%) successfully engrafted while 1 sample failed to grow within 1 year. All 7 engrafted tumors showed full xenograft development up to the third passage on mice, with a decrease in the time required for tumor growth over the generations.
The PDX tumors showed remarkably similar morphology compared to the parental tumors, confirming biological consistency with the original tumor. In addition, the proliferation rate and the angiogenesis pattern evaluated, respectively, by Ki67 and CD31 expression, were reproduced in the PDX tumors. Together, our data indicate that the PDX model of SS was successfully established in our laboratory.

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Author

Lucas Ricardo dos Santos

Boa tarde Sandra, Obrigado! Respondendo as suas perguntas por partes:
  • Quando a gente observa o período de crescimento tumoral (que estabelecemos entre 200 mm³ e 1500 mm³) nós encontramos uma tendência das passagens P1 e P2 apresentarem um período de crescimento tumoral mais curto ou semelhante ao observado na passagem P0.
  • A questão que vejo em relação aos animais imunodeficientes é justamente o fato deles não apresentarem um sistema imunológico completo como ocorre com pacientes com sarcoma sinovial, podendo diferir na resposta imunológica entre o modelo e o próprio paciente. Entretanto, nossos animais não são completamente imunodeficientes (eles são atímicos), contendo ainda resposta imunológica. E assim como todo modelo experimental, o modelo PDX apresenta suas limitações, porém, o que observamos até agora em nosso laboratório e na literatura é que o modelo PDX recapitula as principais características do tumor do paciente ao longo das gerações, permitindo um estudo mais aprofundado do sarcoma sinovial e até mesmo a experimentação de novos quimioterápicos.
  • Não, ainda estamos terminando de estabelecer o modelo em nosso laboratório, temos ainda alguns animais em processo experimental. Por enquanto não temos nada definido, mas pretendemos futuramente implementar pesquisas aplicadas em nosso laboratório.
Consegui ser claro? Teria mais alguma questão que gostaria de abordar?

SANDRA KONIG

Lucas, respondeu muito bem, so não disse como interpreta o fato de observar tempo de crescimento mais curto (tendencia) nas passagens P1 e P2: por que acha que isso vem acontecendo, o que explicaria?
Author

Lucas Ricardo dos Santos

Obrigado! Claro, acabei interpretando a pergunta de outra forma. A meu ver, como os sarcomas são altamente heterogêneos, eles apresentam regiões mais agressivas que outras. Dessa forma, o que acontece ao longo das gerações PDX é que há uma seleção das regiões mais agressivas, fazendo com que haja um encurtamento no tempo de crescimento tumoral.
Institutions
  • 1 Instituto Nacional de Traumatologia e Ortopedia Jamil Haddad, RJ, Brazil
  • 2 Centro de Oncologia Ortopédica / National Institute of Traumatology and Orthopaedics / National Institute of Traumatology and Orthopaedics
  • 3 Teaching and Research Division / National Institute of Traumatology and Orthopaedics / National Institute of Traumatology and Orthopaedics
Keywords
Synovial sarcoma
patient-derived xenograft (PDX)
Translational research