The role of tumor-stroma interactions on desmoplasia and tumorigenicity within a microengineered 3D platform
The role of tumor-stroma interactions on desmoplasia and tumorigenicity within a microengineered 3D platform
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DOI：
10.1016/j.biomaterials.2020.119975
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发表时间：
2020-07-01
期刊：
影响因子：
14
通讯作者：
Nikkhah, Mehdi
中科院分区：
文献类型：
--
作者：
Saini, Harpinder;Eliato, Kiarash Rahmani;Nikkhah, Mehdi
肿瘤微环境已被证明在调节癌症进展中起着至关重要的作用。在肿瘤微环境内的各种细胞类型中，癌症相关成纤维细胞（CAF）是丰富的，用于通过导致增强的肿瘤进展的细胞外基质（ECM）蛋白的过度沉积来调节基质基质的生物物理性质。仍然迫切需要建立一个关于肿瘤-基质细胞相互作用对结缔组织增生和致瘤性的作用的基本框架。在此，我们开发了一个3D微工程化的器官型肿瘤基质模型，该模型与被CAF包埋的胶原基质包围的乳腺癌细胞相结合。我们进一步将我们的平台与原子力显微镜（AFM）相结合，研究了肿瘤侵袭过程中基质硬度的动态变化。我们的研究结果主要证明了CAFs存在时肿瘤进展的增强。此外，我们强调了肿瘤细胞和CAFs之间的串扰对间质结缔组织增生的关键作用，其中我们确定了肿瘤分泌的PDGF-AA/-BB对基质硬度升高的作用。抑制CAFs中PDGFRs的活性导致基质硬度减弱。总体而言，我们的工作提出了一个良好控制的肿瘤微环境模型，能够解剖特定的生物物理和生化信号线索，导致间质结缔组织增生和肿瘤进展。
The tumor microenvironment has been demonstrated to play a crucial role in modulating cancer progression. Amongst various cell types within the tumor microenvironment, cancer associated fibroblasts (CAFs) are in abundance, serving to modulate the biophysical properties of the stromal matrix, through excessive deposition of extracellular matrix (ECM) proteins that leads to enhanced tumor progression. There is still a critical need to develop a fundamental framework on the role of tumor-stromal cell interactions on desmoplasia and tumori-genicity. Herein, we developed a 3D microengineered organotypic tumor-stroma model incorporated with breast cancer cells surrounded by CAF-embedded collagen matrix. We further integrated our platform with atomic force microscopy (AFM) to study the dynamic changes in stromal stiffness during active tumor invasion.Our findings primarily demonstrated enhanced tumor progression in the presence of CAFs. Furthermore, we highlighted the crucial role of crosstalk between tumor cells and CAFs on stromal desmoplasia, where we identified the role of tumor-secreted PDGF-AA/-BB on elevated matrix stiffness. Inhibition of the activity of PDGFRs in CAFs led to attenuation of stromal stiffness. Overall, our work presents a well-controlled tumor microenvironment model capable of dissecting specific biophysical and biochemical signaling cues which lead to stromal desmoplasia and tumor progression.