The Gastric Organoids

  • Challenges in research on human stomach and gastric cancer
  • Opportunities on organoid technology in scientific research
  • Application of gastric organoids in research
  • Example on limitation of current organoid research
  • Some future trends on organoid-related cancer research
  • Selected compositions for gastric epithelial organoid culture recipe by Lab-A-Porter

Challenges in research on human stomach and gastric cancer

The traditional in vitro cancer model used to screen novel therapies is the monolayer 2D cancer cell line culture [3].

      • These models establish unnatural geometric and mechanical constraints by adhering cells to an artificial substrate (either plastic or glass). [3]
      • Such as culture affects cell polarity and therefore, potentially, tumour phenotypes. [3]

Transgenic animal models of gastric cancer tumorigenesis have been advanced. [3]

      • However, these models have all shown limitations connected to genetic background irrelevance, animal resistance and the inability to allow examination of the mechanisms that characterize the aggressive metastasis tumours [3]

Opportunities on organoid technology in scientific research

In the last 10 years, researchers have employed gastric organoids in a wide range of research areas, such as basic stomach biology research, the study of pathogens like Helicobacter pylori and gastric cancer research.

Particularly, patient-derived organoids biobanks of gastric cancer act as a useful tool in studying gastric cancer biology:

      • Gastric cancer ranking as the fifth most common malignancy, the third leading cause of cancer-related deaths. [2]
      • Gastric cancer is a heterogenous disease displaying many different histological and molecular subtypes [1,3]
      • The prognosis of gastric cancer is poor and most advanced forms of the disease remain incurable. [3]
          • Although treatment effectiveness has improved during the past decade, gastric cancer survival rates remain poor. [3]
          • This suggests an urgent need to advance innovative therapies available to gastric cancer patients. [3]

Patient-derived organoids biobanks provide a great advantage over classical 2D cell lines in gastric tumour research [1]

      • Nanki and colleagues have generated 37 PDO lines. [1]
          • They obtained patient-derived organoids of all gastric tumour subtypes except for the Epstein-Barr virus-associated one. [1]
          • Established patient-derived organoids recapitulated the same histopathological features as the original tumour. [1]
      • Yan and colleagues have established 46 PDOs. [1]
          • They classified them into 4 gastric subtypes with comparable mutational spectra. [1]
          • They observed sub-clonal tumour evolution by comparing multiple biopsies obtained from the primary tumour or even metastasis of the same patient. [1]

    Application of gastric organoids in research

    1. Use organoids as a preclinical model

    Organoids are 3D cultures that can retain the morphologies and gene expression profiles of their organs of origin [3].

    1. Use human and mouse organoids for disease modelling

    For example, the use of gastric organoids has facilitated many important discoveries regarding H. pylori pathogenesis [5], pediatric gastric homeostasis and pediatric mucosal diseases [6]

    1. Use patient-derived organoids to personalize medicine for gastric cancer patients

    Patient-derived organoids can be derived from endoscopic tumour biopsies, which maintain heterogeneity in culture. [1] 

      • They can be rapidly established and expanded in a relatively short time for in vitro drug screening experiments, for therapy prediction and guidance. [1]

    Example on limitation of current organoid research

      • Organoids only contain epithelial layers without tissue microenvironments, such as the immune system and nervous system. [5]
      • Fully maturation to adult organs or tissues is a bottleneck needed to be addressed. [5]
      • Dependence on the extracellular matrix or basement membrane extract of current organoids. [5]
      • The culture medium needs to be further refined for the long-term expansion of some organoids. [5]
      • Growth factors or molecular inhibitors in culture medium might have some effects on drug responses of organoids. [5]

    Some future trends on organoid-related cancer research

      • Current data suggest a good predictive value of patient-derived organoids in drug and radiation assays, even if the overall mutational landscape is unknown.[1]
      • The evolution of translational research, through its applications with patient-derived tumour organoid models, makes it emerge as a crucial strategy in personalized medicine programs. [3]
      • New clinical trials are required to further validate the benefits of gastric cancer patient-derived tumour organoids in personalized medicine.[3]
          • To assess the correlation between the in vivo primary tumour response and the ex vivo drug-mediated cytotoxicity. [3]

      Selected compositions for gastric epithelial organoid culture recipe by Lab-A-Porter

      EGF
      EGF is a potent growth factor that stimulates the proliferation of various epidermal and epithelial cells. It has been shown to inhibit gastric secretion and be involved in wound healing.
      FGF-10
      FGF-10 is a heparin-binding growth factor that belongs to the FGF family. Proteins of this family play a central role during prenatal development, postnatal growth and regeneration of a variety of tissues.
      Noggin
      Noggin belongs to a group of diffusible proteins that bind to ligands of the TGF-β family and regulate their activity by inhibiting their access to signalling receptors.       
      R-Spondin-1
      R-Spondin-1 is expressed in certain areas of the developing central nervous system, as well as in the adrenal glands, ovary, testis, thyroid, and trachea.  
      Wnt-3a
      Wnt-3a signalling is essential for various morphogenetic events, including embryonic patterning, cell determination, cell proliferation, CNS development, and cytoskeletal formation.
      Gastrin
      Gastrin is a peptide hormone that is a major physiological regulator of the gastric acid section and a promoter of gastric mucosal growth. 
      Y 27632
      Y-27632 is a selective inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases that selectively competes with ATP for binding to the catalytic site. 
      A 83-01
      A 83-01 is a potent activating receptor-like kinase inhibitor (ALK4 IC50 45nM, ALK5 IC50 12nM, ALK7 IC50 7.5nM). It is a more potent inhibitor of ALK5 than SB 431542 and is reported to inhibit Smad signalling and epithelial-to-mesenchymal transition by transforming growth factor-beta. 
      Nicotinamide
      Nicotinamide is an amide of nicotinic acid, a vitamin of the B complex. In cells, it is incorporated into NADP+ and NAD+, coenzymes for a wide variety of enzymatic oxidation-reduction reactions.
      SB 202190
      SB 202190 is a selective and potent p38 MAP kinases inhibitor, binding to its ATP pocket. It has negligible inhibiting properties on other MAP kinases such as ERKs and JNKs. 
      Xeno-free (animal origin-free) hydrogel system for organoid culture
      Ready-to-use, xeno-free (animal origin-free) hydrogel system for organoid culture
      Biogems, theWell Bioscience and Peprotech products are for research use only (RUO) and are NOT FOR THERAPEUTIC OR DIAGNOSTIC USE. 
       References:

      1. Busslinger, Georg A et al. “The potential and challenges of patient-derived organoids in guiding the multimodality treatment of upper gastrointestinal malignancies.” Open biologyvol. 10,4 (2020): 190274. doi:10.1098/rsob.190274
      2. Seidlitz, Therese et al. “Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine.” Cell death and differentiation vol. 28,1 (2021): 68-83. doi:10.1038/s41418-020-00662-2
      3. Alzeeb, George et al. “Three-Dimensional Culture Systems in Gastric Cancer Research.” Cancersvol. 12,10 2800. 29 Sep. 2020, doi:10.3390/cancers12102800
      4. Lo, Yuan-Hung et al. “A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation.” Cancer discovery vol. 11,6 (2021): 1562-1581. doi:10.1158/2159-8290.CD-20-1109
      5. Xu, Hanxiao et al. “Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine.” Experimental hematology & oncology vol. 7 30. 5 Dec. 2018, doi:10.1186/s40164-018-0122-9

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