ReviewOrganoid model: A new hope for pancreatic cancer treatment?
Graphical abstract
Introduction
Compared with other malignant tumors, pancreatic cancer has a very poor prognosis due to its high degree of malignancy, insidious onset, lack of typical symptoms, anatomical location, low resection rate, and high recurrence rate. The average five-year survival rate is less than 10% and drops to less than 3% in patients with locally advanced or metastatic pancreatic cancer [1]. The pathological types of pancreatic cancer are ductal adenocarcinoma, special types of ductal carcinoma of origin, acinar cell carcinoma, small glandular carcinoma and small cell carcinoma. Among them, pancreatic ductal adenocarcinoma (PDA) is the most common type, accounting for more than 90%. The occurrence and progression of PDA are related to changes in several genes. The activating mutation of KRAS exists in more than 90% of patients and is related to the occurrence of PDA, while inactivation of tumor suppressor genes (CDKN2A, TP53 and SMAD4) accelerates PDA progression [2]. The most common precancerous lesion of PDA is pancreatic intraepithelial neoplasia (PanIN), followed by mucinous cystic tumors and mucinous tumors in the duct. PanIN is a mucous papillary lesion less than 5 mm in diameter and may further develop into infiltrating PDA [3]. Only 20% of PDA patients have an opportunity to undergo surgery, but the remaining patients can only choose conservative medical treatment. In 1996, gemcitabine was approved by the Food and Drug Administration (FDA) as a first-line drug for pancreatic cancer. Burris et al. showed in a randomized trial that compared with traditional chemotherapy regimens, gemcitabine could increase median survival and the 1-year survival rate to 5.65 months and 18%, respectively [4]. Recently, for patients with advanced pancreatic cancer, FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin) and gemcitabine combined with albumin-bound paclitaxel have been approved for use. Compared with gemcitabine alone, FOLFIRINOX with gemcitabine increased the median overall survival by 3.4 months, while the addition of albumin-bound paclitaxel to this combination further increased the median overall survival by 1.8 months [5,6]. To better understand the biological characteristics and disease progression of pancreatic cancer, we developed an organoid model of pancreatic cancer for experimental research.
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Origin and development of organoids
Organoids are a type of special tissue established by culturing stem cells in a unique 3D culture system, of which the structure and function are similar to those of original tissues; the system can either be delivered to a target site or cultured stably for an extended period [[7], [8], [9]]. During the last several years, there has been an increasing number of developed techniques focused on the in vitro growth of 3D as organotypic compositions. These organoids can be grown from embryonic
Organoid formation process
The formation of organoids includes three key steps. First, the key signaling pathways that regulate developmental patterns are inhibited or activated to establish the correct regional characteristics during the differentiation of stem cells. Second, based on established 2D culture methods or inspired by the embryonic development of mice, a medium formulation that allows proper terminal differentiation of the required cell types in the organoid is created. Third, the culture is grown in a way
Culture environment selection
The current parameters for organoid culture mainly include 3D supportive culture (e.g., natural ECM, synthetic matrices), 3D suspension culture (with or without ECM proteins) and air-liquid interface cell pellet culture [30]. Among natural ECMs, Matrigel purified from Engelbreth-Holm Swarm mouse sarcoma is the most widely used type [31]. There are also some less common examples that use collagen type I matrices to derive mammary gland and intestine organoids [32,33]. Among synthetic matrices,
Signal factors required for organoid formation
Most organoids originate from an initial cell population exposed to specific morphogens at specific time points, thereby activating the required developmental signaling pathways. Conversely, when all necessary components are present in the system (the missing components must be provided exogenously so that self-organization can proceed properly), self-organization can be triggered. However, some organoids are exclusively driven by endogenous (system-autonomous) signaling. For instance, the
Cell lines (2D culture)
In 1951, Scherer et al. established the first human cancer cell line from cervical cancer [38]. In 1963, the first human pancreatic cancer cell line was reported, and since then, many PDA cell lines have been established and characterized by their unique molecular phenotypes as well as morphological changes [39]. To date, more than 20 human primary pancreatic tumor cell lines have been established. Cell lines have several main advantages in practice. In some defined media conditions, they are
Basic research application of organoids in pancreatic cancer
Organoids can be combined with 2D cell culture to enhance practicality. The primary cell line is converted into organoids, also known as cell line organoids (CLOs), and this model retains the transcriptome characteristics resembling organoids and PDXs. Shannon et al. 2D-cultured primary PDA cells for two generations, switched them 3D culture, and embedded them in high-concentration ECM; CLOs were then produced after 3–7 days [67]. Later, in the confocal immunofluorescence analysis, it was found
Clinical application of organoids in pancreatic cancer
For patients who have lost the opportunity for surgery, fine needle biopsy(FNB) can be used to obtain a small amount of tumor sample to establish organoid models. Herve et al. conducted a prospective clinical trial using a 22-gauge needle to create a PDA organoid model through endoscopic ultrasound(EUS)- FNB [75]. Among the 38 patients included in the study, 87% of patients successfully established a PDA organoid within 2 weeks, and 66% of patients reached PDA organoid lines for ≥5 passages of
Conclusions
Although the organoid technology available today still has some shortcomings, it still has irreplaceable advantages in the exploration of PDA biology such as its high stability, highly similar characteristics to human PDA cells, ability to predict the progression and prognosis of a disease and role in formulating personalized treatments by testing the effectiveness of and resistance to drugs. To improve the shortcomings of this model, some new points have been proposed: CRISPR-Hot gene editing
Contributions
HDC, QFZ, ZY, YQ, WSL, WYX and GXF collected the related literature and drafted the manuscript. XJY, XWX and SRJ participated in the design of the review and drafted the manuscript. All authors read and approved the final manuscript.
Declaration of Competing Interest
The authors have no competing interests to declare.
Acknowledgments
We thank the editors at AJE (American Journal Experts) for their help in editing the manuscript.
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Contributed equally.