Abstract
Few models exist for studying neuroendocrine tumors (NETs), and there are mounting concerns that the currently available array of cell lines is not representative of NET biology. The lack of stable patient-derived NET xenograft models further limits the scientific community’s ability to make conclusions about NETs and their response to therapy in patients. To address these limitations, we propose the use of an ex vivo 3D flow-perfusion bioreactor system for culturing and studying patient-derived NET surrogates. Herein, we demonstrate the utility of the bioreactor system for culturing NET surrogates and provide methods for evaluating the efficacy of therapeutic agents on human NET cell line xenograft constructs and patient-derived NET surrogates. We also demonstrate that patient-derived NET tissues can be propagated using the bioreactor system and investigate the near-infrared (NIR) dye IR-783 for its use in monitoring their status within the bioreactor. The results indicate that the bioreactor system and similar 3D culture models may be valuable tools for culturing patient-derived NETs and monitoring their response to therapy ex vivo.
Highlights
Neuroendocrine tumors (NETs) are heterogeneous neoplasms originating in diverse anatomical locations, including the lungs, liver, intestines, and adrenal glands
The desmoplastic reaction occurring in ~80% of medullary thyroid cancers is largely comprised of type 1 collagen, and the extracellular matrix (ECM) of the lung is predominated by types I and II collagen [37,38,39]
The presence of NET cells was verified histologically by sectioning and hematoxylin and eosin (H&E) staining of the fixed surrogate matrix composed of 50% bovine type 1 collagen (BT1C)/ 50% Basement Membrane (BM), depicting survival and epithelioid clustering of NET cells (Figure 2C)
Summary
Neuroendocrine tumors (NETs) are heterogeneous neoplasms originating in diverse anatomical locations, including the lungs, liver, intestines, and adrenal glands. NETs constitute over 2% of malignancies, and their incidence and prevalence is steadily increasing [1]. Gastroenteropancreatic NETs (GEP-NETs) recently became the second most prevalent gastrointestinal (GI) malignancy after colorectal cancer [2, 3]. Their variable presentations and relative rarity, at a yearly incidence of 6.8 cases per 100,000 people, can complicate diagnosis [2]. Aberrant bioactive substance secretion by NETs can cause debilitating symptoms such as diarrhea, flushing, cardiac valvular lesions, and metabolic abnormalities [4]. Most NETs are asymptomatic prior to the development of metastases, which are present at diagnosis in 58% of patients [5]. Widespread metastasis at presentation often make complete resections impossible, necessitating systemic therapy [6]
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