Abstract
Development of personalised cancer models to predict response to radiation would benefit patient care; particularly in malignancies where treatment resistance is prevalent. Herein, a robust, easy to use, tumour-on-a-chip platform which maintains precision cut head and neck cancer for the purpose of ex vivo irradiation is described. The device utilises sintered discs to separate the biopsy and medium, mimicking in vivo microvascular flow and diffusion, maintaining tissue viability for 68 h. Integrity of tissues is demonstrated by the low levels of lactate dehydrogenase release and retained histology, accompanied by assessment of cell viability by trypan blue exclusion and flow cytometry; fluid dynamic modelling validates culture conditions. An irradiation jig is described for reproducible delivery of clinically-relevant doses (5 × 2 Gy) to newly-presenting primary tumours (n = 12); the addition of concurrent cisplatin is also investigated (n = 8) with response analysed by immunohistochemistry. Fractionated irradiation reduced proliferation (BrdU, p = 0.0064), increased DNA damage (ƴH2AX, p = 0.0043) and caspase-dependent apoptosis (caspase-cleaved cytokeratin-18) compared to control; caspase-dependent apoptosis was further increased by concurrent cisplatin compared to control (p = 0.0063). This is a proof of principle study showing the response of cancer tissue to irradiation ex vivo in a bespoke system. The novel platform described has the potential to personalise treatment for patients in a cost-effective manner with applicability to any solid tumour.
Highlights
The requirement for targeted and personalised treatment is increasingly apparent; head and neck squamous cell carcinomas (HNSCC) treated with chemotherapy or radiotherapy have 5-year overall survival figures of only 40–60%1,2, with resistance to radiation being a key factor[2]
Maintenance of HNSCC precision cut tumour slices (PCTS) within on-chip devices is in agreement with and extends previous studies[21,24,26,27,40,41]
No significant difference was found in the percentage viability between pre- and post-culture tumour tissue, 25.4% (±3.6) and 20.5% (±1.6) respectively, as determined by trypan blue exclusion
Summary
The requirement for targeted and personalised treatment is increasingly apparent; head and neck squamous cell carcinomas (HNSCC) treated with chemotherapy or radiotherapy have 5-year overall survival figures of only 40–60%1,2, with resistance to radiation being a key factor[2]. Some centres screen for HPV-positive cancers as this is the strongest predictor of locoregional control and disease specific survival[4,5,6], and phase III treatment de-escalation trials are underway[7] Aside from these trials, no technologies or screening methodologies, aiming to personalise therapy for HNSCC are currently employed. Cell lines have been widely employed[9]; increasing evidence highlights the critical nature of the 3D structure[10,11], which has led to engineered tissues being constructed from layered cell lines[12,13,14] Whilst these engineered tissues hold significant benefits over traditional monolayer culture and have been integrated into on-chip systems[15,16], in vivo complexities are still not entirely mirrored, as the full gamut of cell types and extracellular matrix found in primary tissues are absent. A major advantage of the current device over those previously described by Zambon[23] and Atac[25], who both maintain primary tissue (adipose, and skin and hair respectively) under continuous flow, is that the system is simple and highly reliable, and can be transferred into a clinical setting
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