4.6 Article

Organotypic Co-Cultures as a Novel 3D Model for Head and Neck Squamous Cell Carcinoma

期刊

CANCERS
卷 12, 期 8, 页码 -

出版社

MDPI
DOI: 10.3390/cancers12082330

关键词

HNSCC; 3D organotypic co-culture model; invasion; HPV

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资金

  1. Heidelberg University's Medical Faculty
  2. German Cancer Aid [70112000]
  3. iMED-HNSCC Funding Program of the Helmholtz Initiative on Personalized Medicine

向作者/读者索取更多资源

Background: Head and neck squamous cell carcinomas (HNSCC) are phenotypically and molecularly heterogeneous and frequently develop therapy resistance. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and to overcome treatment failure.Methods: We developed a three-dimensional organotypic co-culture (3D-OTC) model for HNSCC that maintains the architecture and cell composition of the individual tumor. A dermal equivalent (DE), composed of healthy human-derived fibroblasts and viscose fibers, served as a scaffold for the patient sample. DEs were co-cultivated with 13 vital HNSCC explants (non-human papillomavirus (HPV) driven,n= 7; HPV-driven,n= 6). Fractionated irradiation was applied to 5 samples (non-HPV-driven,n= 2; HPV-drivenn= 3). To evaluate expression of ki-67, cleaved caspase-3, pan-cytokeratin, p16(INK4a), CD45, proportional to smooth muscle actin and vimentin over time, immunohistochemistry and immunofluorescence staining were performed Patient checkup data were collected for up to 32 months after first diagnosis.Results: All non-HPV-driven 3D-OTCs encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primaries and 3D-OTCs were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth patterns (i.e., invasive, expansive, silent). Cancer-associated fibroblasts and leukocytes could be detected for up to 21 days. HPV DNA was detectable in both primary and 3D-OTCs (day 14) of HPV-driven tumors. However, p16(INK4a)expression levels were varying. Morphological alterations and radioresistant tumor cells were detected in 3D-OTC after fractionated irradiation in HPV-driven and non-driven samples.Conclusions: Our 3D-OTC model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth and might, in the future, serve as a platform to perform sensitivity testing upon treatment to predict therapy response.

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