RESUMEN
Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features. We used an established spheroid model generated from the human colon adenocarcinoma cell line Caco2 to study the effects of T3 and TRα1 on spheroid formation, growth, and response to conventional chemotherapies. Our results show that T3 treatment and/or increased TRα1 expression in spheroids impaired the response to FOLFIRI and conferred a survival advantage. This was achieved by stimulating drug detoxification pathways and increasing ALDH1A1-expressing cells, including CSCs, within spheroids. These results suggest that clinical evaluation of the thyroid axis and assessing TRα1 levels in CRCs could help to select optimal therapeutic regimens for patients with CRC. Proposed mechanism of action of T3/TRα1 in colon cancer spheroids. In the control condition, TRα1 participates in maintaining homeostatic cell conditions. The presence of T3 in the culture medium activates TRα1 action on target genes, including the drug efflux pumps ABCG2 and ABCB1. In the case of chemotherapy FOLFIRI, the increased expression of ABC transcripts and proteins induced by T3 treatment is responsible for the augmented efflux of 5-FU and Irinotecan from the cancer cells. Taken together, these mechanisms contribute to the decreased efficacy of the chemotherapy and allow cells to escape the treatment. Created with BioRender.com .
Asunto(s)
Camptotecina/análogos & derivados , Neoplasias del Colon , Fluorouracilo , Células Madre Neoplásicas , Esferoides Celulares , Receptores alfa de Hormona Tiroidea , Triyodotironina , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Células CACO-2 , Neoplasias del Colon/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Triyodotironina/farmacología , Leucovorina/farmacología , Leucovorina/uso terapéutico , Camptotecina/farmacología , Camptotecina/uso terapéutico , Fenotipo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Familia de Aldehído Deshidrogenasa 1/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Retinal-Deshidrogenasa/metabolismo , Retinal-Deshidrogenasa/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genéticaRESUMEN
A pivotal role of thyroid hormones and their nuclear receptors in intestinal development and homeostasis have been described, whereas their involvement in intestinal carcinogenesis is still controversial. In this perspective article we briefly summarize the recent advances in this field and present new data regarding their functional interaction with one of the most important signaling pathway, such as WNT, regulating intestinal development and carcinogenesis. These complex interactions unveil new concepts and will surely be of importance for translational research.
Asunto(s)
Regulación de la Expresión Génica , Genes erbA , Neoplasias Intestinales/patología , Intestinos/patología , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , Vía de Señalización Wnt , Homeostasis , Humanos , Neoplasias Intestinales/genética , Neoplasias Intestinales/metabolismo , Intestinos/metabolismo , Receptores de Hormona Tiroidea/genéticaRESUMEN
Colorectal cancers are characterized by heterogeneity and a hierarchical organization comprising a population of cancer stem cells (CSCs) responsible for tumor development, maintenance, and resistance to drugs. A better understanding of CSC properties for their specific targeting is, therefore, a pre-requisite for effective therapy. However, there is a paucity of suitable preclinical models for in-depth investigations. Although in vitro two-dimensional (2D) cancer cell lines provide valuable insights into tumor biology, they do not replicate the phenotypic and genetic tumor heterogeneity. In contrast, three-dimensional (3D) models address and reproduce near-physiological cancer complexity and cell heterogeneity. The aim of this work was to design a robust and reproducible 3D culture system to study CSC biology. The present methodology describes the development and optimization of conditions to generate 3D spheroids, which are homogenous in size, from Caco2 colon adenocarcinoma cells, a model that can be used for long-term culture. Importantly, within the spheroids, the cells which were organized around lumen-like structures, were characterized by differential cell proliferation patterns and by the presence of CSCs expressing a panel of markers. These results provide the first proof-of-concept for the appropriateness of this 3D approach to study cell heterogeneity and CSC biology, including the response to chemotherapy.
