Cancer is a major public health problem worldwide. Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality. Historically, the mechanisms of ...tumour initiation and progression in the gastrointestinal tract have been studied using cancer cell lines in vitro and animal models. Traditional cell culture methods are associated with a strong selection of aberrant genomic variants that no longer reflect the original tumours in terms of their (metastatic) behaviour or response to therapy. Organoid technology has emerged as a powerful alternative method for culturing gastrointestinal tumours and the corresponding normal tissues in a manner that preserves their genetic, phenotypic and behavioural traits. Importantly, accumulating evidence suggests that organoid cultures have great value in predicting the outcome of therapy in individual patients. Herein, we review the current literature on organoid models of the most common gastrointestinal cancers, including colorectal cancer, gastric cancer, oesophageal cancer, liver cancer and pancreatic cancer, and their value in modelling tumour initiation, metastatic progression and therapy response. We also explore the limitations of current organoid models and discuss how they could be improved to maximally benefit basic and translational research in the future, especially in the fields of drug discovery and personalized medicine.
Mouse and human urothelial cancer organoids Mullenders, Jasper; de Jongh, Evelien; Brousali, Anneta ...
Proceedings of the National Academy of Sciences - PNAS,
03/2019, Letnik:
116, Številka:
10
Journal Article
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Bladder cancer is a common malignancy that has a relatively poor outcome. Lack of culture models for the bladder epithelium (urothelium) hampers the development of new therapeutics. Here we present a ...long-term culture system of the normal mouse urothelium and an efficient culture system of human bladder cancer cells. These so-called bladder (cancer) organoids consist of 3D structures of epithelial cells that recapitulate many aspects of the urothelium. Mouse bladder organoids can be cultured efficiently and genetically manipulated with ease, which was exemplified by creating genetic knockouts in the tumor suppressors Trp53 and Stag2. Human bladder cancer organoids can be derived efficiently from both resected tumors and biopsies and cultured and passaged for prolonged periods. We used this feature of human bladder organoids to create a living biobank consisting of bladder cancer organoids derived from 53 patients. Resulting organoids were characterized histologically and functionally. Organoid lines contained both basal and luminal bladder cancer subtypes based on immunohistochemistry and gene expression analysis. Common bladder cancer mutations like TP53 and FGFR3 were found in organoids in the biobank. Finally, we performed limited drug testing on organoids in the bladder cancer biobank.
Cervical cancer is a common gynecological malignancy often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study the cervical epithelium and the ...cancers derived thereof. Here we describe a long-term culturing protocol for ecto- and endocervical epithelia that generates 3D organoids that stably recapitulate the two tissues of origin. As evidenced for HSV-1, organoid-based cervical models may serve to study sexually transmitted infections. Starting from Pap brush material, a small biobank of tumoroids derived from affected individuals was established that retained the causative human papillomavirus (HPV) genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutic agents and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches.
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•Establishment of long-term organoid cultures from human ecto- and endocervix•Promising platform for modeling STIs, as evidenced for HSV-1•Pap brush collection as a successful method for cervical tumoroid derivation•Cervical tumoroids display disease hallmarks, such as causative HPV infection
Human-based model systems that faithfully recapitulate cervical cancer and causative HPV infection are scarce and often inadequate. With the advances in organoid technology, Lõhmussaar et al. have now extended this knowledge to the cervix, describing a successful derivation of endo- and ectocervical organoids as well as tumoroids from the associated malignancies.
Abstract
Genome-wide mutation analyses have revealed that specific anti-cancer drugs are highly mutagenic to cancer cells, but the mutational impact of anti-cancer therapies on normal cells is not ...known. Here, we examine genome-wide somatic mutation patterns in 42 healthy adult stem cells (ASCs) of the colon or the liver from 14 cancer patients (mean of 3.2 ASC per donor) that received systemic chemotherapy and/or local radiotherapy. The platinum-based chemo-drug Oxaliplatin induces on average 535 ± 260 mutations in colon ASC, while 5-FU shows a complete mutagenic absence in most, but not all colon ASCs. In contrast with the colon, normal liver ASCs escape mutagenesis from systemic treatment with Oxaliplatin and 5-FU. Thus, while chemotherapies are highly effective at killing cancer cells, their systemic use also increases the mutational burden of long-lived normal stem cells responsible for tissue renewal thereby increasing the risk for developing second cancers.
Effective predictive biomarkers are needed to enable personalized medicine and increase treatment efficacy and survival for cancer patients, thereby reducing toxic side effects and treatment costs. ...Patient-derived organoids (PDOs) enable individualized tumour response testing. Since 2018, 17 publications have examined PDOs as a potential predictive biomarker in the treatment of cancer patients. We review and provide a pooled analysis of the results regarding the use of PDOs in individualized tumour response testing, focusing on evidence for analytical validity, clinical validity and clinical utility. We identify future perspectives to accelerate the implementation of PDOs as a predictive biomarker in the treatment of cancer patients.
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to ...improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
The presence of peritoneal metastases (PM) in patients with colorectal cancer (CRC) is associated with an extremely poor prognosis. The diagnosis of PM is challenging, resulting in an underestimation ...of their true incidence. While surgery can be curative in a small percentage of patients, effective treatment for non-operable PM is lacking, and clinical and pre-clinical studies are relatively sparse. Here we have defined the major clinical challenges in the areas of risk assessment, detection, and treatment. Recent developments in the field include the application of organoid technology, which has generated highly relevant pre-clinical PM models, the application of diffusion-weighted MRI, which has greatly improved PM detection, and the design of small clinical proof-of-concept studies, which allows the efficient testing of new treatment strategies. Together, these developments set the stage for starting to address the clinical challenges. To help structure these efforts, a translational research framework is presented, in which clinical trial design is based on the insight gained from direct tissue analyses and pre-clinical (organoid) models derived from CRC patients with PM. This feed-forward approach, in which a thorough understanding of the disease drives innovation in its clinical management, has the potential to improve outcome in the years to come.
The liver's cellular functions are sustained by a hierarchical, segmentally-organized vascular system. Additionally, liver lymphatic vessels are thought to drain to perihepatic lymph nodes. ...Surprisingly, while recent findings highlight the importance of organ-specific lymphatics, the functional anatomy of liver lymphatics has not been mapped out. In literature, no segmental or preferential lymphatic drainage patterns are known to exist. We employ a novel murine model of liver lymphangiography and in vivo microscopy to delineate the lymphatic drainage patterns of individual liver lobes. Our data from blue dye liver lymphangiography show preferential lymphatic drainage patterns: Right lobe mainly to hepatoduodenal ligament lymph node 1 (LN1); left lobe to hepatoduodenal ligament LN1 + LN2 concurrently; median lobe showed a more variable LN1/LN2 drainage pattern with increased (sometimes exclusive) mediastinal thoracic lymph node involvement, indicating that part of the liver can drain directly to the mediastinum. Upon ferritin lymphangiography, we observed no functional communication between the lobar lymphatics. Altogether, these results show the existence of preferential lymphatic drainage patterns in the murine liver. Moreover, this drainage can occur directly to mediastinal lymph nodes and there is no interlobar lymphatic flow. Collectively, these data provide the first direct evidence that liver lymphatic drainage patterns follow segmental anatomy.
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