Fonseca-Filho V C N, Katayama M L H, Lyra E C, Maria D A, Basso R A, Nonogaki S, Guerra J M, Maistro S, Góes J C G S, Folgueira M A A K
Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Departamento de Radiologia e Oncologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo - USP, Avenida Dr. Arnaldo, 251, Cerqueira César, CEP 01246-000, São Paulo, SP, Brazil.
Departamento de Mastologia, Instituto Brasileiro de Controle do Câncer - IBCC, Avenida Alcântara Machado, 2576, Parque da Mooca, CEP 03102-002, São Paulo, SP, Brazil.
Braz J Biol. 2017 Nov;77(4):856-867. doi: 10.1590/1519-6984.04016. Epub 2017 May 4.
Calcitriol antiproliferative effects were observed in xenografts of breast cancer cell lines, however they were not yet investigated in tumorgrafts, consisting of freshly collected breast cancer samples xenografted into animals. To establish a tumorgraft model, from freshly collected breast cancer samples, which were directly implanted in nude mice, to study calcitriol effects.
Breast cancer samples collected from 12 patients were orthotopically implanted into nude mice. Animals were treated with weekly intratumoral injections of calcitriol 3 μg/Kg, which was previously shown to induce peak serum calcitriol levels in the predicted therapeutic range.
Success engraftment rate was 25%. Tumorgrafts were established from aggressive (HER2 positive or histological grade 3) highly proliferative samples and original tumor characteristics were preserved. Calcitriol highly induced its target gene, CYP24A1, indicating that the genomic vitamin D pathway is active in tumorgrafts. However, no differences in the expression of proliferation and apoptosis markers (BrdU incorporation, Ki67, CDKN1A, CDKN1B, BCL2 expression) were observed in these highly proliferative tumor samples.
Tumorgrafts seem a promising model to explore other calcitriol doses and regimens, considering the heterogeneity of the disease and microenvironment interactions.
在乳腺癌细胞系异种移植模型中观察到了骨化三醇的抗增殖作用，但尚未在由新鲜采集的乳腺癌样本异种移植到动物体内形成的肿瘤移植模型中进行研究。为了建立肿瘤移植模型，将新鲜采集的乳腺癌样本直接植入裸鼠体内，以研究骨化三醇的作用。
将从12例患者采集的乳腺癌样本原位植入裸鼠体内。动物每周接受一次瘤内注射骨化三醇，剂量为3μg/Kg，先前研究表明该剂量可使血清骨化三醇水平达到预测治疗范围内的峰值。
成功植入率为25%。肿瘤移植模型由侵袭性强（HER2阳性或组织学3级）、高增殖性的样本建立，且保留了原发肿瘤的特征。骨化三醇高度诱导其靶基因CYP24A1，表明基因组维生素D途径在肿瘤移植模型中具有活性。然而，在这些高增殖性肿瘤样本中，未观察到增殖和凋亡标志物（BrdU掺入、Ki67、CDKN1A、CDKN1B、BCL2表达）的表达存在差异。
考虑到疾病的异质性和微环境相互作用，肿瘤移植模型似乎是探索其他骨化三醇剂量和给药方案的一个有前景的模型。
