Molecular genetic alterations in adrenal and extra-adrenal pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas are neuroendocrine neoplasias of neural crest origin. Genetic mutations that are characterized in other human neoplasms are rarely seen in these tumors. About 10% of the patients with pheochromocytomas and paragangliomas present with a family history of von Hippel-Lindau disease (VHL), Multiple endocrine neoplasia type 2 (MEN2), one of the three familial paraganglioma syndromes (PGL; PGL1, PGL3, PGL4), or neurofibromatosis type 1 (NF1). In an even higher percentage, a genetic predisposition is involved in the development of these tumors. The genes of hereditary tumor syndromes such as the aforementioned ones are also ideal to study the molecular pathogenesis in the sporadic counterparts. Many studies have been undertaken to identify important secondary genetic events that contribute to the tumorigenesis of pheochromocytoma or paraganglioma, but a comprehensive review of these data is lacking. Recent findings of CGH and LOH studies provided new starting points to unravel the pathogenesis and progression of these tumors. This review presents an overview of our current understanding of the molecular pathogenesis of pheochromocytoma and paraganglioma. This work has been presented at the Endocrine Pathology Society meeting of the 92nd annual USCAP meeting in Washington DC, March 22, 2003.     

Mechanisms of Panax ginseng in preventing rat pheochromocytoma cells from apoptosis

Aims of the study

Although ginseng root possesses dominant central therapeutic effects and has recently undergone investigations for treating different neuronal diseases, most of its mechanisms are still unknown. Therefore, the neuroprotective mechanisms of ginseng were studied.

Materials and methods

The protection afforded by different methanol extracts of Panax ginseng (PG) was tested in a serum deprivation-induced apoptotic model using neuronal-like pheochromocytoma (PC12) cells. An MTT assay, annexin V-FITC staining, and Western blots were, respectively, applied to identify the viability of cells, the apoptotic form of cell death, and the activity of antiapoptotic signaling.

Results

The known antiapoptotic PI3-K/Akt and MEK/ERK pathways in this system were ruled out due to failure of LY 294002 and PD 98059 to block the protection by PG. A protein kinase A (PKA) inhibitor was found to block the protection by PG and PG-induced CREB phosphorylation, suggesting that the PKA/CREB pathway mediates the protective effect of PG. Downregulation of classical and novel PKCs failed to block the protection by PG, while an atypical PKC inhibitor blocked protection by PG.

Conclusions

PKA and atypical PKC are important for the protection afforded by PG in preventing serum deprivation-induced PC12 cell apoptosis.     

Ligusticum chuanxiong as a potential neuroprotectant for preventing serum deprivation-induced apoptosis in rat pheochromocytoma cells: Functional roles of mitogen-activated protein kinases

Ethnopharmacological relevance

Ligusticum chuanxiong (LC) as a common component in many traditional Chinese medicinal formulas and decoctions has been used to treat different central nervous diseases, suggesting a neuroprotective function.

Aim of the study

To investigate the functional roles of mitogen-activated protein kinases (MAPKs) in mediating the neuroprotection of LC.

Materials and methods

Different extractions of LC were applied with or without MAPK inhibitor to test their protection against serum deprivation-induced apoptosis in rat neuronal-like pheochromocytoma (PC12) cells as revealed by an MTT assay or Hoechst staining. Western blot was used to identify the activations of MAPKs.

Results

The most effective butanol extraction (LC-BuOH) was used in the following experiments. LC-BuOH reversed serum deprivation-induced decreased phosphorylation of extracellular signal-regulated kinase (ERK) and increased phosphorylation of c-Jun NH₂-terminal kinase (JNK) and p38, the family of MAPKs. A PKA inhibitor, blocked the protection of LC-BuOH and partially blocked LC-BuOH-induced alterations in MAPKs, suggesting that the LC-BuOH regulates MAPKs through both PKA-dependent and -independent pathways. Although PD 98059, an inhibitor of MEK which activates ERK, blocked LC-BuOH-induced ERK phosphorylation, it did not block the protection of LC-BuOH.

Conclusions

LC-BuOH mediates protection by suppressing JNK/p38 instead of activating ERK activity.     

嗜铬细胞瘤手术治疗(附120例报告)

９７３年９月至１９９５年６月手术治疗嗜铬细胞瘤１２０例，其中良性１１３例（９４０％），恶性７例（５９％）。Ｂ超、ＣＴ对肾上腺嗜铬细胞瘤的诊断率分别为８９０％、９７０％。强调充分的术前准备，严密的术中及术后监测是手术治疗的三个重要环节。本组无症状嗜铬细胞瘤占７５％。恶性嗜铬细胞瘤的治疗仍以手术治疗为主。     

热休克蛋白抑制剂对嗜铬细胞瘤裸鼠移植瘤的抑制作用

目的 本研究通过观察热休克蛋白90（HSP90）抑制剂17-丙烯胺-17～去甲氧格尔德霉素（17-AAG）对大鼠嗜铬细胞瘤裸鼠移植瘤生长的影响,探讨17-AAG对大鼠嗜铬细胞瘤肿瘤生长和血管生成的抑制作用.方法 用大鼠嗜铬细胞瘤细胞PC12接种于裸鼠皮下,建立移植瘤模型,15d后将荷瘤裸鼠随机分为2组,每组12只,分别为实验组（腹腔注射17-AAG 40mg/kg）和对照组（腹腔注射生理盐水10mL/kg）,用药3周,第4周后测量裸鼠移植瘤体积和重量,采用免疫组化方法检测肿瘤组织中HSP90、信号转导和转录活化因子3（STAT3）、表皮生长因子受体-2（ERBB2）的表达,采用western blotting法检测肿瘤组织中HSP90、STAT3、ERBB2的表达.结果 第4周时,对照组的移植瘤体积为5070.13±630.42mm3,重量为7.94±1.20g;实验组的移植瘤体积为2218.80±336.29mm3,重量为3.29±0.57g,实验组抑瘤率为58.6％,两组移植瘤体积和重量存在显著差异（P＜0.05）.实验组肿瘤组织的HSP90、STAT3、ERBB2表达明显低于对照组（P＜0.05）.结论 17-AAG对大鼠嗜铬细胞瘤裸鼠移植瘤有明显抑制作用,并可降低肿瘤组织中HSP90和STAT3、ERBB2的表达.     

Difficulté diagnostic d’un choc cardiogénique sur une sub-occlusion thrombotique de l’IVA. Un train peut en cacher un autre !

The pheochromocytome is a localized tumor at the level of the medullosurrenale in 85% of the cases. The clinical presentation is very variable. Severe Heart failure presentation can be the mode of revelation in 2% of the cases. We present the case of a patient admitted for refractory cardiogenic shock correlated to pheochromocytome tumor. The difficulty of this rare clinical presentation was to confirm rapidly and in emergency this diagnosis in the same time when the patient presents a persistante and severe cardiogenic chock after finding a sub-occluded and thrombotic LAD coronary artery and which was treated by thrombectomy and coronary revascularization. The surgical treatment of this tumor is considered to be a quickly saving treatment. It allows a fast recovery of the cardiac function.     

Recurrent severe acute apical-sparing left ventricular dysfunction in a young woman: Don’t forget pheochromocytoma

A 35-year-old woman was admitted for second cardiogenic shock. She had no cardiovascular risk factors. Recurrent acute myocarditis was suggested. Recurrent acute myocardial dysfunctions in a young patient suggested pheochromocytoma. Initial trans-thoracic echocardiography showed a typical severe basal and mid-ventricular left ventricular dysfunction but preserved apical contractility. Total CT-scan evidenced a right suprarenal mass advocating for a pheochromocytoma. Biology confirmed the diagnosis of pheochromocytoma. These images illustrate the rare but acute and typical clinical outcomes, and echocardiography findings.     

心脏嗜铬细胞瘤的诊断及外科治疗(附3例报告)

目的：探讨心脏嗜铬细胞瘤的诊断与外科治疗。方法：心脏嗜铬细胞瘤3例，男性2例，女性1例，年龄分别为17、19及35岁。患者均以头痛、心悸、大汗及血压增高就诊。术前24小时尿儿茶酚胺检查均升高，分别经超声心动、CT及冠脉造影等检查证实心脏不同部位有占位性病变，3例生长抑素受体显像阳性。3例均在体外循环下行肿瘤切除术。结果：手术顺利，无手术死亡，术后病理证实为心脏嗜铬细胞瘤。术后随访28～48个月患者头痛、心悸、大汗及高血压明显改善。1例术后原心脏部位生长抑素受体高表达病灶有进展，1例24小时尿儿茶酚胺水平未降至正常水平。结论：心脏嗜铬细胞瘤极为罕见，诊断过程困难，手术切除肿瘤是治疗心脏嗜铬细胞瘤有效的方法，对不能手术直接切除的心脏嗜铬细胞瘤患者，自体心脏移植是一种值得考虑的手术选择。     

嗜铬细胞瘤35例临床分析

目的 提高对嗜铬细胞瘤临床特点的认识。方法 回顾分析35例嗜铬细胞瘤患者的临床表现、生化检查、影像学诊断。结果 临床表现为阵发性高血压占60％、持续性高血压占34、3％、血压正常占5.71％；临床上有三联症状（头痛、心悸、多汗）之一的占94．3％；尿VMA检查35例．阳性率85．7％，B超检查29例，阳性率89.7％，CT检查18例，阳性率100％，MRI检查19例，阳性率100％．131^I-MIBG检查25例，阳性率100％；35例均行手术治疗并经病理证实，肿瘤位于肾上腺的占85.7％．异位嗜铬细胞瘤的占14．3％．其中复发性异位嗜铬细胞瘤1例。结论尿VMA检查是嗜铬细胞瘤定性诊断的依据，B超、CT、MRI、131^I-MIBG检查为定位诊断的依据．术后病理学检查是确诊嗜铬细胞瘤的依据。