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The
neuroendocrine phenotype, cellular plasticity,
and the search for genetic switches:
Redefining the diffuse neuroendocrine system
by Robert Day & Michel Salzet
Dépt de Pharmacologie, Institut de Pharmacologie de Sherbrooke,
Université de Sherbrooke, Québec, Canada,
Laboratoire de Neuroimmunologie des Annélides, Université des
Sciences et Technologies de Lille, France.
Submitted:
October 4, 2002 Accepted: October 5, 2002
Key
words:
APUD cells, immune system, endocrine, paraneuron, gene
switches, cell plasticity
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Abstract
The
term neuroendocrine has been used to define cells that secrete
their products in a regulated manner, in response to a specific
stimulus. The neuroendocrine system includes neurons and endocrine
cells sharing a common phenotypic program characterized by
the expression of markers such as neuropeptides, chromogranins,
neuropeptide processing enzymes SPC2 and SPC3 (subtilase-like
pro-protein convertases) or dense core secretory granules.
Various theories such as the APUD (amine precursor uptake
decarboxylation) concept, the diffuse neuroendocrine system
(DNES) or the paraneuron concept have been put forth to classify
neuroendocrine cells as a cohesive group. Neuroendocrine characteristics
have been used as evidence of a common embryological origin
for normal and neoplastic cells. However, it is now recognized
that neuroendocrine characteristics can be observed in various
cell types, such as immunocytes, that are not of a common
embryological origin with either neurons or endocrine cells.
We propose to redefine previous “neuroendocrine”
concepts to include the notion that activation of specific
genetic switches can lead to the expression of a partial or
full neuroendocrine phenotype in a variety of cell types,
including immune cells.
* * *
We
can no longer define neuroendocrine cells simply based on their
content of neuropeptides or chromogranins. When appropriately
stimulated, cells that are neither neural or endocrine can express
either a neuroendocrine phenotype or an immune cell phenotype.
These data provide evidence that genotypic switches are present
in cells that were previously thought to be irrevocably differentiated.
Claude Bernard (1813–1878) originally recognized the importance
of the ‘internal environment’ of the organism and
the ‘internal secretion’ in relation to the maintenance
of homeostasis. The origin of these internal secretions was
later understood through the studies of the pancreas by Paul
Langerhans (1869) and of the gut mucosa by Heidenhain (1870)
and Kultschitzky (1897). The demonstration of silver-staining
granules in chromaffin cells led to the discovery of other such
cells, which were found in dispersed patterns throughout different
tissues. Friedrich Feyrter (1938) reported the presence of rather
pale cells (helle Zellen) distributed widely throughout the
body using staining techniques, which led to the concept of
a ‘diffuse endocrine system’. It was not till much
later that these basic observations were crystallized into a
unique concept. It was suggested that these cells secrete chemical
messengers acting in a paracrine or endocrine manner. Everson
Pearse developed the APUD concept (amine precursor uptake and
decarboxylation) based on the finding of identical biogenic
amines and peptides hormones in neurons and in the dispersed
endocrine cells located in different organs [1,2.]. Based on
histological and biochemical features, Pearse grouped into a
single entity widely separated cells present either in classic
endocrine organs or isolated in sites dispersed throughout the
body, whose function was to act as a diffuse neuroendocrine
system (DNES) [3]. The major features included the production
of polypeptide hormones as well as the presence of a set of
cytochemical and ultrastructural characteristics. Pearse went
further by suggesting that all cells comprising this system
shared a common embryological origin, namely the neural crest
[1]. An important conceptual notion was advanced that these
cells were functionally coordinated in their actions, providing
communication with the nervous system. Coordinated actions of
the DNES with autonomic and somatic nervous systems would affect
or control the functions of internal organs. This original and
very useful concept was expanded with the advent of improved
staining methodologies, the advancement of molecular biological
techniques and the growing list of neuropeptides and cell markers
that appeared to be particular to neural or endocrine cells
[4–6]. These markers were studied extensively especially
to establish the origins of various tumors. The presence of
a marker, such as chromogranin A, was viewed as evidence of
the neuroendocrine origin of the tumor cells. Other postulates,
such as that of the ‘paraneuron’ concept, introduced
by Fujita, re-enforced the notion of a common embryological
origin of all neuroendocrine cells, namely the neuroectoderm
[7].
Neuropeptides
are not expressed uniquely in neuroendocrine cells
... ...
Cellular
plasticity and gene switches
... ...
Redefining
the neuroendocrine concept
... ...
Conclusions
... ...
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