Tumour microenvironment in pheochromocytoma and paraganglioma

Martinelli, Serena; Amore, Francesca; Canu, Letizia; Maggi, Mario; Rapizzi, Elena

doi:10.3389/fendo.2023.1137456

Cited by 6 publications

(5 citation statements)

References 189 publications

(173 reference statements)

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“…Along with morphological studies, molecular genetic analysis is carried out (Gimenez‐Roqueplo et al, 2023; A. Snezhkina et al, 2022; A. V. Snezhkina et al, 2020). Currently, the role of the microenvironment in the progression and metastasis of malignant tumors is widely argued (Hanahan & Weinberg, 2011; Koontongkaew, 2013; Martinelli et al, 2023). Tumor commonly progresses changing cell functions in the microenvironment: fibroblasts acquire properties of immunosuppressors, macrophages acquire tumorogenic functions, lymphocytes are gradually reprogrammed, and can exhibit pro‐tumor activity, MCs can turn into powerful pro‐inflammatory cells that affect tumor progression (Ribatti, 2023; Zhang et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural features of tumor‐associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck

Chekmaryova,

Kalinin,

Kostin

et al. 2024

Microscopy Res & Technique

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The mechanisms of the pathogenesis of neck paraganglioma (PGL) and the possible role of mast cells (MCs) in its development and metastasis are still poorly understood. We analyzed MCs' morphologic characterization, activation, and the properties of their cytoplasmic/released granules in PGLs, using light and transmission electron microscopy. Paragangliomas showed a large tumor‐associated MC population both in the connective tissue layers of the tumor and between the tumor cells. Notably, MCs were presented by a high expression of specific proteases, size variation, polymorphism, and variable ultrastructural phenotype of granules. A massive number of granules were released surrounding the degranulated MCs while the integrity of MC membrane was maintained. Granules were electron‐dense with or without a membrane, ranging from 0.2 to 0.8 μm in diameter. MC plasmalemma was not found at the site of MC‐collagen fibrils contact, whereas the secretome and fibrils were directly contacted. We observed direct and mediator‐based interactions between MCs and paraganglioma cells. The latter preserved their membrane integrity when MC granules were not in proximity. The effects of the MC secretome on the paraganglioma microenvironment demonstrated its pathogenetic role in tumor progression and allow its application to new diagnostic criteria and the development of protocols for personalized therapy.Research Highlights Ultrastructural analysis reveals novel regulatory effects of mast cells via diverse secretory pathways on the pathogenesis of parasympathetic paraganglioma, including fibrous extracellular matrix remodeling and mediator‐based interactions between MCs and cells of the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Ultrastructural features of tumor‐associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck

Chekmaryova,

Kalinin,

Kostin

et al. 2024

Microscopy Res & Technique

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“…Adrenal tumors (ATs) are a rare type of tumor that usually occurs in the cortex or medulla of the adrenal gland ( 1 ). Depending on their type and size, these tumors can be benign or malignant ( 2 ). ATs can cause many symptoms, including high blood pressure, palpitations, headaches, insomnia, anxiety, and obesity ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of machine-learning models for the difficulty of retroperitoneal laparoscopic adrenalectomy based on radiomics

Sun,

Yao,

Wang

et al. 2023

Front. Endocrinol.

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ObjectiveThe aim is to construct machine learning (ML) prediction models for the difficulty of retroperitoneal laparoscopic adrenalectomy (RPLA) based on clinical and radiomic characteristics and to validate the models.MethodsPatients who had undergone RPLA at Shanxi Bethune Hospital between August 2014 and December 2020 were retrospectively gathered. They were then randomly split into a training set and a validation set, maintaining a ratio of 7:3. The model was constructed using the training set and validated using the validation set. Furthermore, a total of 117 patients were gathered between January and December 2021 to form a prospective set for validation. Radiomic features were extracted by drawing the region of interest using the 3D slicer image computing platform and Python. Key features were selected through LASSO, and the radiomics score (Rad-score) was calculated. Various ML models were constructed by combining Rad-score with clinical characteristics. The optimal models were selected based on precision, recall, the area under the curve, F1 score, calibration curve, receiver operating characteristic curve, and decision curve analysis in the training, validation, and prospective sets. Shapley Additive exPlanations (SHAP) was used to demonstrate the impact of each variable in the respective models.ResultsAfter comparing the performance of 7 ML models in the training, validation, and prospective sets, it was found that the RF model had a more stable predictive performance, while xGBoost can significantly benefit patients. According to SHAP, the variable importance of the two models is similar, and both can reflect that the Rad-score has the most significant impact. At the same time, clinical characteristics such as hemoglobin, age, body mass index, gender, and diabetes mellitus also influenced the difficulty.ConclusionThis study constructed ML models for predicting the difficulty of RPLA by combining clinical and radiomic characteristics. The models can help surgeons evaluate surgical difficulty, reduce risks, and improve patient benefits.

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“…Approximately 80% of PPGLs are linked to genetic mutations, often indicating a genetic predisposition ( 2 , 8 ). Gene expression profiling enables the classification of PPGLs into three distinct clusters based on their molecular characteristics: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3).…”

Section: Introductionmentioning

confidence: 99%

“…Cluster-3 is characterized by the activation of the WNT signaling pathway, potentially contributing to increased cellular proliferation and invasiveness. Notably, Cluster-3 accounts for approximately 5%-10% of PPGLs cases and also includes tumors with mutations in the CSDE1 and the MAML3 fusion genes ( 2 , 12 , 13 ). In the three clusters, Cluster 1 exhibits the most prominent risk of metastasis ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…Pheochromocytomas (pcc) and paragangliomas (PGL) (PPGLs) are infrequent neuroendocrine tumors deriving from chromaffin cells. Pheochromocytoma originates in the adrenal medulla, accounting for approximately 80%-85% of cases, while paraganglioma arises externally from sympathetic paraganglia dispersed throughout the body, constituting around 15%-20% of cases (1)(2)(3). Despite their low incidence rate (roughly 6.6 cases per million individuals annually) (4), these tumors bear noteworthy clinical significance due to their potential to induce excessive catecholamine secretion, precipitating perilous cardiovascular complications and myocardial degenerative alterations.…”

Section: Introductionmentioning

confidence: 99%

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The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma

Wang,

Liu,

et al. 2023

Front. Endocrinol.

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Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.

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Tumour microenvironment in pheochromocytoma and paraganglioma

Cited by 6 publications

References 189 publications

Ultrastructural features of tumor‐associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck

Ultrastructural features of tumor‐associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck

Development and validation of machine-learning models for the difficulty of retroperitoneal laparoscopic adrenalectomy based on radiomics

The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma

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