Secretion of Chromogranin A by Peptide-Producing Endocrine Neoplasms

O’Connor, Daniel T.; Deftos, Leonard J.

doi:10.1056/nejm198605013141803

Cited by 447 publications

(223 citation statements)

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“…On the other hand, only two conflicting studies have been published so far on patients with primary HPT. O'Connor and Deftos (2), in their preliminary report, described abnormally high CgA plasma levels in a series of nine patients with primary HPT, but subsequently Nanes et al (15) failed to demonstrate a significant increase of CgA levels in patients with parathyroid adenoma, although elevated values occurred in HPT patients with sporadic or familial parathyroid hyperplasia and in those with Tommasetti et al (8). In the latter series, the percentage of MEN 1 patients with CgA elevations (53%) was, however, lower than ours (94%), but some of the patients had previously undergone pancreatic surgery (8).…”

Section: Discussionmentioning

confidence: 97%

“…However, most studies have been performed in patients with sporadic GEP NETs, although it is well known that these tumors can occur as a part of multiple endocrine neoplasia syndrome type 1 (MEN 1), which also includes parathyroid and pituitary tumors. Nevertheless, data on the plasma CgA pattern in patients with this syndrome are scanty (8,10), and the available studies have not evaluated patients with sporadic forms of primary hyperparathyroidism (HPT) or pituitary tumors, although high plasma CgA levels have sometimes been reported in these diseases (2,11,12).…”

Section: Introductionmentioning

confidence: 99%

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Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1

Peracchi

Conte

Gebbia

et al. 2003

European Journal of Endocrinology

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Objective: As circulating chromogranin A (CgA) has been claimed to be the best general neuroendocrine marker so far available, we evaluated the usefulness of CgA determination in the clinical assessment of patients with sporadic gastro-entero-pancreatic neuroendocrine tumors (GEP NETs) or multiple endocrine neoplasia type 1 (MEN 1). Design and methods: Plasma CgA levels were measured using a commercial enzyme-linked immunosorbent assay in 61 patients with sporadic GEP NET and in 25 with MEN 1 including 16 with GEP NET. Controls were 50 healthy volunteers, 46 patients with pituitary adenoma and 35 patients with primary hyperparathyroidism. Results: The cutoff value for CgA established in our healthy subjects (as mean+2 S.D.) was 20 U/l. CgA levels were above the normal range in 71/77 patients with sporadic or MEN 1-related GEP NETs (92%), in four out of nine MEN 1 patients without GEP NETs (44%), and only in 22/81 control patients with pituitary or parathyroid disease (27%). Furthermore, CgA levels of over 100 U/l occurred in 36/77 patients with GEP NETs (47%) and only in one patient with a non-functioning pituitary adenoma. In the patients with GEP NETs, both tumor burden and secretory activity affected CgA levels, and successful surgical resection was associated with markedly decreased CgA values. Conclusions: Plasma CgA was confirmed to be a reliable marker for GEP NETs. Moreover, in MEN 1 patients the finding of very high CgA levels strongly suggests the presence of a GEP NET, as both primary hyperparathyroidism and pituitary adenomas rarely cause marked CgA increases.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1

Peracchi

Conte

Gebbia

et al. 2003

European Journal of Endocrinology

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“…9G, arrowheads) by the coexpression of chromogranin A, a widely used marker for malignant cells of neuroendocrine origin (Fig. 9G, arrows) (25).…”

Section: Identification Of a Subset Of Malignant Pancreatic β-Cells Ementioning

confidence: 99%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, plateletderived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development.However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

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“…The relatively high basal plasma CgA concentration may also be a function of its multiple potential endocrine tissue sources. 41 In any event, plasma CgA changes are not informative for modest changes of exocytotic catecholamine release within the physiologic range (e.g., Figures 2,[4][5][6].…”

Section: Takiyyuddin Et Al Catecholamine Release In Vivo 187mentioning

confidence: 99%

Is physiologic sympathoadrenal catecholamine release exocytotic in humans?

et al. 1990

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In cultured cells and isolated perfused organs, catecholamines are coreleased with chromogranin A (CgA) from adrenal chromaffin cells and sympathetic neurons. The corelease suggests that exocytosis is the mechanism of catecholamine secretion. To investigate whether physiologic catecholamine secretion is exocytotic in humans, we measured plasma norepinephrine, epinephrine, and CgA responses to differentiated stimuli of sympathoadrenal discharge. The CgA radioimmunoassay antibody recognized authentic CgA in normal human adrenal chromaffin vesicles. Insulin-induced hypoglycemia and caffeine ingestion, in decreasing order of potency, selectively stimulated epinephrine release from the adrenal medulla. During hypoglycemia, plasma levels of epinephrine and CgA rose, and peak plasma levels of epinephrine and CgA correlated, suggesting that gradations in epinephrine release represented gradations in exocytosis. However, significant increments in plasma CgA were not observed after caffeine ingestion. Furthermore, the rise of CgA levels during hypoglycemia lagged 60 minutes behind those of epinephrine. A less-pronounced temporal dissociation between CgA and epinephrine release was also shown in isolated chromaffin cells in vitro. Selective adrenal vein catheterization suggested a barrier to CgA transport across the adrenal capillary wall. Short-term, high-intensity dynamic exercise, assumption of the upright posture, prolonged low-intensity dynamic exercise, and smoking, in decreasing order of potency, stimulated norepinephrine release from sympathetic nerve endings. Only the first sympathetic neuronal stimulus resulted in significant increments in plasma CgA, increments considerably less than those attained during adrenal medullary activation by insulin hypoglycemia.During high-intensity exercise, peak plasma norepinephrine and CgA levels correlated, suggesting that gradations in norepinephrine release represented gradations in exocytosis. The human adrenal medulla was a far more prominent tissue source of CgA than human sympathetic nerves -adrenal medullary homogenates contained 97-fold more CgA(,ug/g) than sympathetic nerve homogenates. In conclusion, catecholamine secretion during selective stimulation of either sympathetic nerves or the adrenal medulla is, at least in part, exocytotic. Furthermore, stimulation of the former resultsin comparatively modest changes in plasma CgA compared with changes attained during stimulation of the latter. CgA appears to be transported by a route different from that of catecholamines from adrenal medullary chromaffin cells to the circulation in vivo. (Circulation 1990;81:185-195) C atecholamine release in isolated cells and by corelease of the catecholamine storage vesicle organs is exocytotic from both adrenal medcore constituents chromogranin A (CgA)2,5 and dopa-

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Secretion of Chromogranin A by Peptide-Producing Endocrine Neoplasms

Cited by 447 publications

References 20 publications

Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1

Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Is physiologic sympathoadrenal catecholamine release exocytotic in humans?

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