[Von Hippel-Lindau disease].

The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.

https://www.mdpi.com/2073-4409/9/1/27/pdf

Fibronectin in Cancer: Friend or Foe

Peritoneal response to various kinds of injury involves loss of peritoneal mesothelial cells (PMC), danger signalling, epithelial-mesenchymal transition and mesothelial-mesenchymal transition (MMT). Encapsulating peritoneal sclerosis (EPS), endometriosis (EM) and peritoneal metastasis (PM) are all characterized by hypoxia and formation of a vascularized connective tissue stroma mediated by vascular endothelial growth factor (VEGF). Transforming growth factor-β1 (TGF-β1) is constitutively expressed by the PMC and plays a major role in the maintenance of a transformed, inflammatory micro-environment in PM, but also in EPS and EM. Persistently high levels of TGF-β1 or stimulation by inflammatory cytokines (interleukin-6 (IL-6)) induce peritoneal MMT, adhesion formation and fibrosis. TGF-β1 enhances hypoxia inducible factor-1α expression, which drives cell growth, extracellular matrix production and cell migration. Disruption of the peritoneal glycocalyx and exposure of the basement membrane release low molecular weight hyaluronan, which initiates a cascade of pro-inflammatory mediators, including peritoneal cytokines (TNF-α, IL-1, IL-6, prostaglandins), growth factors (TGF-α, TGF-β, platelet-derived growth factor, VEGF, epidermal growth factor) and the fibrin/coagulation cascade (thrombin, Tissue factor, plasminogen activator inhibitor [PAI]-1/2). Chronic inflammation and cellular transformation are mediated by damage-associated molecular patterns, pattern recognition receptors, AGE-RAGE, extracellular lactate, pro-inflammatory cytokines, reactive oxygen species, increased glycolysis, metabolomic reprogramming and cancer-associated fibroblasts. The pathogenesis of EPS, EM and PM shows similarities to the cellular transformation and stromal recruitment of wound healing.

Hypoxia, cytokines and stromal recruitment: parallels between pathophysiology of encapsulating peritoneal sclerosis, endometriosis and peritoneal metastasis.

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors. Pheochromocytomas arise from chromaffin cells in the adrenal medulla, and PGLs arise from chromaffin cells in the ganglia of the autonomic nervous system. Paragangliomas originate from sympathetic or parasympathetic ganglia in the abdomen, thorax, and pelvis. The majority of PCC and sympathetic PGL are endocrine active tumors causing clinical symptoms by secreting excess catecholamines (norepinephrine, epinephrine, dopamine) and their metabolites. The incidence of PCC and PGL ranges between 2 and 8 per million, with a prevalence between 1:2500 and 1:6500. It peaks between the 3rd and 5th decades of life, and approximately 20% of cases are pediatric patients. The prevalence among patients with hypertension in outpatient clinic ranges between 0.1-0.6% in adults and between 2-4.5% in the pediatric age group. 10-49% of these tumors is detected incidentally in imaging techniques performed for other reasons. However, 4-8% of adrenal incidentalomas are PCCs. Of these neuroendocrine tumors, 80-85% are PCCs and 15-20% are PGLs. Up to 40% of patients with PCC and PGL has disease-specific germline mutations and the situation is hereditary. Of 60% of the remaining sporadic patients, at least 1/3 has a somatic mutation in predisposing genes. 8% of the sporadic cases, 20-75% of the hereditary cases, 5% of the bilateral, adrenal cases, and 33% of the extra-adrenal cases at first presentation are metastatic. Although PCCs and PGLs have scoring systems for histological evaluation of the primary tumor, it is not possible to diagnose whether the tumor is malignant since there is no histological system approved for the biological aggressiveness of this tumor group. Metastasis is defined as the presence of chromaffin tissue in non-chromaffin organs, such as lymph nodes, liver, lungs and bone. Although most of the PCC and PGL are benign, the metastatic disease may develop in 15-17%. Metastatic disease is reported between 2-25% in PCCs and 2.4-60% in PGLs. The TNM staging system of the American Joint Committee on Cancer (AJCC) was developed to predict the prognosis, based on the specific anatomical features of the primary tumor and the occurrence of metastasis.

/pdf/pheochromocytoma-and-paraganglioma-from-epidemiology-to-305avreq1v.pdf

Pheochromocytoma and Paraganglioma: From Epidemiology to Clinical Findings.

Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is a clear example. Here, we present our efforts to decipher the role of von Hippel-Lindau tumor suppressor protein (pVHL) in cancer insurgence. We collected high quality information about both pVHL mutations and interactors to investigate the association between patient phenotypes, mutated protein surface and impaired interactions. Our data suggest that different phenotypes correlate with localized perturbations of the pVHL structure, with specific cell functions associated to different protein surfaces. We propose five different pVHL interfaces to be selectively involved in modulating proteins regulating gene expression, protein homeostasis as well as to address extracellular matrix (ECM) and ciliogenesis associated functions. These data were used to drive molecular docking of pVHL with its interactors and guide Petri net simulations of the most promising alterations. We predict that disruption of pVHL association with certain interactors can trigger tumor transformation, inducing metabolism imbalance and ECM remodeling. Collectively taken, our findings provide novel insights into VHL-associated tumorigenesis. This highly integrated in silico approach may help elucidate novel treatment paradigms for VHL disease.

/pdf/genotype-phenotype-relations-of-the-von-hippel-lindau-tumor-2qh5bh40bl.pdf

Genotype-phenotype relations of the von Hippel-Lindau tumor suppressor inferred from a large-scale analysis of disease mutations and interactors.

The Von Hippel–Lindau (VHL) disease is an autosomal dominant disorder characterized by the predisposition for multiple tumors caused by germline mutations in the tumor suppressor gene VHL. This disease is associated with a high morbidity and mortality and presents a variable expression, with different phenotypes from family to family, affecting different organs during the lifetime. The main manifestations of VHL are hemangioblastomas of the central nervous system and retina, renal carcinomas and cysts, bilateral pheochromocytomas, cystic and solid tumors of the pancreas, cystadenomas of the epididymis, and endolymphatic sac tumors. The discovery of any of the syndrome components should raise suspicion of this disease and other stigmas must then be investigated. Due to the complexities associated with management of the various VHL manifestation, the diagnosis and the follow-up of this syndrome is a challenge in the clinical practice and a multidisciplinary approach is needed. The particular relevance to endocrinologists is the detection of pheochromocytomas in 35% and islet cell tumors in 17% of VHL patients, which can be associated with hypertension, hypoglycemia, cardiac arrhythmias, and carcinoid syndrome. The purpose of this review is to define the Von Hippel–Lindau syndrome addressing its clinical aspects and classification, the importance of genetic counseling and to propose a protocol for clinical follow-up.

L. C. L. Berbel

Papers

Von Hippel–Lindau disease: a single gene, several hereditary tumors