PO.TB10.18 · 肿瘤生物学
脱细胞肺生物基质模型用于研究转移性乳腺癌器官选择性趋向性的微环境调控
Decellularized lung biomatrix models to investigate microenvironmental regulation of organ-selective tropism in metastatic breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：乳腺癌是女性中最常被诊断的恶性肿瘤，也是癌症相关死亡的主要原因。转移性疾病是乳腺癌死亡的主要原因，其中肺是关键的转移器官。尽管从传统二维（2D）系统到体内模型的多种肿瘤模型已被用于研究乳腺癌肺转移，但它们并未完全重现肺特异性微环境。
方法：为研究器官微环境对乳腺癌细胞趋向性的作用和影响，我们使用亲本型和肺转移型MDA-MB-231细胞变体，以多种细胞密度（25 k、15 k、5 k、2.5 k、1 k和0.5 k细胞/cm²）接种于脱细胞肺基质上。脱细胞肺生物基质支架采用灌注方案从大鼠获取。为评估细胞活性，对所有条件进行了基于ATP的发光测定，并归一化至相应的对照条件（在无肺生物基质情况下培养的细胞）。
结果：归一化的ATP测量显示，脱细胞肺生物基质对亲本型和肺转移型MDA-MB-231细胞的代谢活性产生了不同程度的调节。在几乎所有接种密度和生物基质浓度下，肺转移型变体总体上表现出比亲本系更高的生长速度，提示肺来源的基质通过增强激活增殖信号通路的细胞-基质相互作用，为转移细胞提供了更有利的微环境。这一差异在较高的细胞接种密度和较高的脱细胞肺生物基质蛋白浓度下最为明显。在25 k、15 k和5 k细胞/cm²时，肺转移型细胞在200和300 μg/cm²下相对于亲本细胞表现出归一化代谢活性的明显增加。相反，在2.5 k、1 k和0.5 k细胞/cm²的细胞密度下，在5天培养期内，亲本细胞和转移细胞的归一化ATP值在所有基质蛋白密度下均相当。正在进行的工作旨在进一步表征肺模拟支架中的细胞活性和细胞-基质信号通路。
结论：我们基于脱细胞肺生物基质支架的离体模型表明，肺特异性微环境线索相对于亲本细胞选择性地增强了肺转移性乳腺癌细胞的代谢活性，支持器官特异性转移偏好的微环境调控。
查看英文原文 English abstract
Background: Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer-related death in women. Metastatic disease is the main cause of breast cancer mortality, with lung as a key metastatic organ. Although a variety of tumor models, ranging from conventional two-dimensional (2D) systems to in vivo models, have been used to study breast cancer lung metastasis, they do not fully recapitulate lung specific microenvironment.
Methods: To study the role and impact of organ microenvironment on the tropism of breast cancer cells, we used parental and lung-metastatic variants of MDA-MB-231cells by seeding the various cell densities (25 k, 15 k, 5 k, 2.5 k, 1 k, and 0.5 k cell/cm²) on decellularized lung matrices. The decellularized lung biomatrix scaffolds were harvested from rats using perfusion protocol. To assess cell activity, ATP-based luminescence assays were performed for all conditions and normalized to the corresponding control condition (cells cultured in the absence of lung biomatrix).
Results: Normalized ATP measurements showed that decellularized lung biomatrix differentially modulated the metabolic activity of parental and lung-metastatic MDA-MB-231 cells. Across almost all seeding densities and biomatrix concentrations, the lung-metastatic variant generally exhibited higher growth velocity than the parental line, suggesting that the lung-derived matrix provides a more favorable microenvironment for the metastatic cells through enhanced cell-matrix interactions that activate proliferative signaling pathways. This difference was most evident at higher cell seeding densities and higher protein concentrations of decellularized lung biomatrix. At 25 k, 15 k, and 5 k cells/cm², the lung-metastatic cells displayed a clear increase in normalized metabolic activity relative to the parental cells at 200 and 300 µg/cm². In contrast, at cell densities of 2.5 k, 1 k, and 0.5 k cells/cm², normalized ATP values for parental and metastatic cells were comparable across all matrix protein densities within 5 days culture period. Ongoing work aims to further characterize cellular activities and cell-matrix signaling pathways in the lung-mimetic scaffolds.
Conclusion: Our ex vivo model based on decellularized lung biomatrix scaffolds demonstrates that lung specific microenvironmental cues selectively enhance the metabolic activity of lung-metastatic breast cancer cells relative to parental cells, supporting microenvironmental regulation of organ specific metastatic preference.
利益披露 Disclosure
K. Goodarzi, None..
Y. Yin, None.