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Tumour microenvironment in pheochromocytoma and paraganglioma.

ABSTRACT: Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.

SUBMITTER: Martinelli S

PROVIDER: S-EPMC10073672 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Tumour microenvironment in pheochromocytoma and paraganglioma.

Martinelli Serena S Amore Francesca F Canu Letizia L Maggi Mario M Rapizzi Elena E

Frontiers in endocrinology 20230322

Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastat ...[more]

PMID: 37033265

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Project description:Simple Summary Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours and are often non-metastatic. However, no effective treatment is available for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available concerning whether metformin is also able to inhibit PPGL metastatic spread. A tumour is a very complex system, comprising not only cancer cells, but also other cells that all together form the so-called tumour microenvironment. Cancer-associated fibroblasts are residential or recruited fibroblasts, transformed by cancer cells, to promote tumour growth and spread. Therefore, the interplay between tumour cells and cancer-associated fibroblasts has become an interesting target for cancer therapy. Here, we demonstrate that metformin has different effects on cancer cells and fibroblasts, providing evidence that metformin may hold promise for altering tumour microenvironment homeostasis. Improving our knowledge on malignant tumour microenvironment properties could lead to develop complementary strategies to target tumour spread and progression. Abstract Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.

Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

Tumour microenvironment in pheochromocytoma and paraganglioma.

Publications

Tumour microenvironment in pheochromocytoma and paraganglioma.

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