Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
SCREEN FOR RISK FOR GASTRIC ADENOCARCINOivIA
Background of the Invention
The United States government has certain rights in this invention
by virtue of a grant from the National lnstitutes of Health NIDDKD to
James R. Goldenring.
Gastric cancer worldwide is the second highest cause of death
from cancer. While rates of gastric cancer have been decreasing in the
United States, gastric cancer prevalence remains high in other parts of the
world, especially in Asia. Presently, patients in endemic regions for
gastric center, especially Japan and China. undergo screenine hwpper
endoscopy. There is no alternative at present for discovery of early
cancer other than by endoscopy. Grading of these endoscopies is based
solely on hematoxylin and eosin staining. There are no prognostic
markers that could indicate those at risk for future cancer development.
Therefore, while biopsies can reveal early gastric cancers, patients in high
risk regions who are initially negative by endoscopy must be followed
with endoscopies to rule out future developments.
The epidemiological association between chronic H. pylori
infection and gastric carcinoma is now well established, such that the
Working Group Meeting of the International Agency for Research on
Cancer with the World Health Organization recently classified
Helicobacter pylori as a group 1 human gastric carcinogen (Peura. D.A.
Gatroenterology. 113, S4-S8 (1997)). Parsonnet and colleagues reported
that 84% of patients with gastric cancer had serum antibodies against H.
pylori, as opposed to 66% of uninfected matched controls (Parsonnet, et
al. New Eng. J. Med. 325, 1127-1131 (1991}). H. pylori infection
induces a chronic gastritis progressing to atrophic gastritis, foveoiar
hyperplasia and intestinal metaplasia (Mobley, H.T.L. Gastronenterology.
I13, S21-S28 (1997)}. Recent studies have indicated that chronic gastritis
associated with Helicobacter pylori contributes to the development of
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gastric adenocarcinoma (Peura, D.A. Gatroenterology. 113, S4-S8
(1997); Parsonnet. et al. New Eng. J. Med. 325, 1127-1131 (1991);
Forman et al. Br. J. Med. 302, 1302-1305 (1991); Nomura, et al. New
Eng. J. Med. 325, 1132-1136 (199I))_ Nevertheless, the mechanism of
progression from chronic gastritis to malignant disease remains unclear,
and the relationship of intestinal metaplasia, H. pylori infection and the
development of cancer continues to be controversial. Moreover, while an
association between gastric cancer and infection with H. pylori has
recently been established, the cell of origin for gastric adenocarcinoma is
controversial. This does not establish a mechanism between the bacteria
and the cancer, and provides little or no guidance for correlating
treatment of, or risk associated with, ll. pylori as it relates to
development of gastric cancer.
It is therefore an object of the present invention to provide
screening methods for early gastric cancer.
It is a further object of the present invention to provide means for
assessing the degree of early gastric cancer and for screening and
following patients at risk for gastric cancer.
It is a still further object of the present invention to provide means
for serological testing for patients at risk of gastric cancer.
Summary of the Invention
It has been determined that a specific metaplastic lineage that
contains immunoreactivity for a trefoil poiypeptide, spasrnolytic peptide,
is associated with and gives rise to the vast majority of human
adenocarcinomas. The identification of this Spasmolytic Polypeptide
Expressing Metaplasia (SPEM) is a major factor for grading of biopsies
of the stomach to assess risk for gastric cancer. It also forms the basis of
a method for serological screening for those at risk for gastric cancer. In
a preferred embodiment, antibodies to spasmoIytic peptide (hSP) are used
in immunostaining of biopsies of gastric tissue obtained by endoscopy for
grading biopsies. Those patients having these cells, characterized by a
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morphology more typical of a type of cell present normally iri'the '
intestine and not stomach, Brunner's gland cells, are at risk of developing
adenocarcinoma. Since these cells express hSP, antibodies or nucleic acid
probes hybridizing to mRNA encoding hSP, can be used for rapid
detection of the cells in tissue biopsies. The antibodies can also be used
in serological tests for screening and following patients at risk for gastric
cancer. In combination with evidence of previous or present invention
with H. pylori, the tests are predictive of the likelihood of developing
adenocarcinoma.
Detailed Description of the Invention
Metaplastic cell lineages arising in response to chronic injury are
precursors for the evolution of dysplasia and adenocarcinoma. This
sequence is well characterized in the case of the Barrett's epithelium, a
columnar specialized intestinal metaplasia in the distal esophagus of
patients with esophageal reflux (Haggitt, R.C. Hum. Pathol. 25, 982-993
(1994)). While a subtype of intestinal metaplasia has been associated with
gastric adenocarcinoma (Dixon, et al. Am. J. Surg. Pathol. 20, 1161-1181
(1996); Filipe et al. Int. J. Cancer. 57, 324-329 (1994)); Correa, P.
Cancer Res. 48, 3554-3560 (1988)), the link between these lineages and
the evolution of gastric adenocarcinoma has not been clear. It has now
been determined that there is an association between SPEM, detectable in
biopsies based on the presence of cells having a morphology similar to
Brunner's gland cells, and adenocarcinoma. Although normal cells in the
stomach, such as mucus neck cells, express hSP, these cells are not
predictive of adenocarcinoma.
I. Methods and Reagents for Screening
A. Histolo~y of the Gastric Tissues
Presently, gastric mucosal biopsies are fixed in formalin and
embedded in paraffin. Microtome sections of tissues are then stained with
hematoxylin and eosin. These stained slides are examined for loss of
parietal cells (oxyntic atrophy), ulceration, inflammatory infiltrates, and
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alterations in cell lineages including iricreased~numbers ot'sui-face mucous
cells (foveolar hyperplasia), the presence of goblet cells (intestinal
metaplasia), as well as dysplasia and adenocarcinoma. Dysplasia and
adenocarcinoma are judged by changes in nuclear morphology, loss of
cytoplasmic space, loss of polarity and invasion of submucosa or
vasculature. Brunner's glands are not present in the normal stomach but
can be observed in the duodenum.
B. Markers of SPEM
Small peptides displaying a cysteine-rich module (termed P-domain
or trefoil motif) from a group of peptides, including BCEI, expressed
from the pS2 gene; hITF, expressed from the TFF3 gene; and hSP ,
expressed from the SML1 gene. These peptides are abundantly expressed
at mucosal surfaces of specific tissues and are associated with the
maintenance of surface integrity. (Schmitt, et al., Cytogenet. Cell Genet.
72(4), 299-302 (1996)). Human spasmolytic peptide (hSP) was identified
by Romasetto, et al., EMBO J., 9(2), 407-414 (1990), based on homology
to pancreatic spasmolytic polypeptide, sequenced and determined to be
separately encoded on the genome from pS2. The gene sequence and
amino acid sequences of hSP can be obtained from GenBank, accession
number 1477545. Both are present in normal stomach epithelium. The
patterns and timing of the expression of the trefoil peptides are different
from each other. It is thought that S2 plays an important role in the
proliferation of intestinal epithelial cells during the acute phase of mucosal
ulceration, whereas ITF may be involved in differentiation of the cells,
particularly to form goblet cells, during the recovery phase of acute
colitis. (Itoh, et al., Biochem. J. 318(Pt 3), 939-944 (1996))
Immunostaining for SP in the intact mucosa has been determined to be
confined to the mucous neck cells, but following exposure to stress it was
significantly enhanced and occurred also in the cells of the basal region of
gastric glands, as reported by Konturek, et al., Regul. Pept. 68(1), 71-79
( 1997). Konturek, et al. ( I 997) proposed that SP plays an important role in
healing of stress-induced gastric lesions, possibly by the acceleration of
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the mucosal repair, the enhancement of mucosal blood flow and the
inhibition of gastric secretion.
It has now been determined that SP is a marker of metaplastic cells
having a morphology similar to those of Brunner's gland cells. These
cells can be identified by histoIogical examination. However, the
identification of SPEM with spasmolytic peptide immunostaining is easier,
more sensitive and rapid. Therefore, detection of metaplastic cells
expressing SP provides a means for identification of those at risk who
would need further follow-up. Furthermore, since the SPEM lineage is
IO often extensive, quantitation of serum spasmolytic polypeptide IevCls by
either radioimmunoassay or ELISA should be useful to stratify patients at
risk and provide a serological method for identifying and following
patients at risk for developing adenocarcinoma.
SPEM can be detected using antibodies or antibody fragments
prepared by standard techniques. The studies described in the examples
were performed with a mouse monoclonal IgM anti-human spasmolytic
polypeptide developed by Drs. Richard Poulsom and Nicholas Weight at
the Imperial Cancer Research Fund, London, UK. Antibodies specifically
directed towards utility in RIA and ELISA have also been developed.
Either monoclonal or polyclonal antibodies can be used. Antibodies can
be labelled using any detectable marker, including radiolabels, fluorescent
labels, dyes, enzyme-chromogenic substrate systems, and other means
commercially available.
SPEM can also be detected using nucleic acid probes which
hybridize under standard hybridization conditions, as described for
example, by Maniatis, et al. Molecular Cloning: A Laboratory Manual
(Cold Spring Harbor Laboratory), to mRNA encoding SP. These can be
labeled using standard labelling techniques for detection of bound nucleic
acid.
Alternatively, or in addition, other markers of these cells can be
used to screen for the presence of SPEM in gastric tissue biopsies.
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For serlogical assay of SP, serum would be obtained from fasting
patients. SP levels would be determined using either radioimmunoassay
or enzyme-linked immunoassay. A standard curve would be used for
known amounts of recombinant SP (Lays Thimm, Novartis Corporation).
Patients with elevated levels of SP in serum would be investigated for the
presence of SPEM by endoscopy. Alternatively, patients with elevated
serum SP and documented SPEM could be followed following treatment
of H. pylori by serial serum determinations of SP.
C. Detection of H. Dvlori Infection
Since H. pylori is known to be associated with an increased
incidence of adenocarcinoma of the stomach, efficacy of screening can be
further enhanced by testing for previous or present H. pylori infection. H.
pylori infection would be determined by either CLO test at the time of
biopsy or H. pylori serology with the same sample used for SP
determination.
II. Patients to be Screened and Screening Procedures
SP detection, such as immunohistochemistry, can be used to
determine the presence of SPEM in endoscopic biopsies as well as
brushings obtained either through endoscopy or blind per oral intubation.
As noted above, gastric cancer screening, especially in Asian
countries, is a major focus for clinical care. Presently, the only impact of
medicine on gastric cancer is through early detection of low grade tumors
and early resection for cure. High grade tumors have uniformly dismal
prognosis with median survival less than one year. No significant effect
of adjuvant chemotherapy has been noted. The addition of spasmolytic
polypeptide immunostaining of biopsies and the identification of SPEM
provides a means for identifying those at risk for developing cancer in the
future. Similarly, the use of spasmolytic peptide serology should provide
a blood test for identification of those at risk. Thus, the use of
spasmolytic polypeptide immunostaining could significantly decrease the
number of screening endoscopies, focus screening endoscopies, and,
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through serology testing, facilitate screening of large populations a risk in
Asia and other countries with high cancer incidence.
The present invention will be further understood by reference to
the following non-limiting examples.
Background
Wang and colleagues examined the influences of chronic
Heticobacter gastritis using Helicobacter fells to infect the gastric
epithelium of CS7BL/6 mice (Wang, et al. Gastroenterology. 114, 675-
689 (1998)). Infection with H. fells produced a chronic gastritis with
pathologic features similar to human infection with H. pylori including
marked loss of parietal and chief cell populations, in addition to
elaboration of an aberrant mucous cell lineage (Lee, et al.
Gastroenterotogy. 99, 1315-1323 (1990); Fox, et al., Gastroenterology.
110, I55-166 (1996)). Wang, et al. (1998) reported that an aberrant
metaplastic cell lineage with morphological characteristics similar to
runner's glands of the duodenum develops in the tundic mucosa oC mice
infected with H. fells. This metaplastic lineage expresses the trefoil
peptide spasmolytic polypeptide (SP). This expanded lineage stained with
antibodies against spasmolytic polypeptide (SP), a trefoil peptide secreted
from mucous neck cells in the normal fundic mucosa (Wang, et al.
(1998); Thim, L. FEBS Lett. 250, 85-90 (1989)). Importantly, the H.
fells-induced SP-expressing metaplastic (SPEM) lineage did not show
morphological characteristics of mucous neck cells, but rather
demonstrated morphology more reminiscent of Brunner's glands of the
duodenum (Wang (1998)).
Hynothesis
Given the results in mice, studies were designed to investigate
whether H. pylori infection would induce a similar aberrant SP-expressing
lineage in human fundic mucosa. Given the epidemiological association
of Helicobacter sp. infection with gastric cancer, it was hypothesized that
this SP-expressing metaplastic (SPEM) lineage may represent a precursor
to or appear commensurate with gastric adenocarcinoma.
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Summary of Results
The results of these studies showed that the SPEM lineage was
present in 68% of fundic biopsies from patients with fundic H. pylori-
associated gastritis, but was absent in biopsies of fundic mucosa from
patients without H. pylori infection. In a review of archival samples from
22 resected gastric adenocarcinomas, the SPEM lineage was found in
91 % of cases, typically located in mucosa adjacent to the carcinoma or
areas of dysplasia. Importantly, 56% of samples showed SP
immunoreactivity within dysplastic cells. These data indicate not onty a
strong association between the SPEM lineage and gastric adenocarcinoma,
but that SPEM cells represent the metapiastic lineage responsible for
development of this tumor in patients with H. pylori.
Example 1: Detection of SP levels in gastric fundic biopsies.
Ten fundic biopsies from H. pylori negative patients and 17
biopsies from patients with H. pylori colonization in the fundus were
examined. All biopsies demonstrated H/K-ATPase-immunostaining
parietal cells and contained no gastrin-immunoreactive cells, confirming
the authenticity of fundic mucosal biopsies. In all of the H. pvlori-
infected biopsies specimens, the presence of H. pylori was cont firmed by
Giemsa staining of tissue sections. The histological characteristics of
these biopsies are summarized in Table I.
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CA 02345663 2001-03-28
Table I: Histological analysis of fundic biopsies from H. pylori
(Hp) negative and H. pylon positive patients.
HP Negative HP Positive
Absent Present Absent
Present
Foveolar hyperplasia 10 0 4 13
Oxyntic atrophy 10 0 6 11
Mononuclear infiltrates 8 2 1
16*
SPEM 10 0 6 11
Foveolar hypetplasia was assessed in sections stained for
pS2 as the presence of surface cells in greater than 25% of the
gland length. Oxyntic atrophy was assessed in sections stained for
H/K-ATPase as a decrease in parietal cell density to less than half
the gland length. Mononuclear infiltrates were assessed in H&E
stains.
*3 of 16 N. pylori (Hp) positive patients demonstrated
organized lymphoid aggregates. SPEM was assessed in sections
stained for hSP.
Gastric fundic biopsies were stained for SP. 10 ~.m sections from
paraffin-embedded biopsies of fundic mucosa from H. pylori uninfected
and H. pylori infected patients were stained for hSP with a monoclonal
murine anti-HSP Elia, et al. Histochem. J. 26, 644-647 (1994)).
Dewaxed paraffin sections were blocked with 5 % goat serum in phosphate
buffered saline and then incubated with anti-hSP (I:50) for one hour at
room temperature. Indirect immunohistochemical detection was then
performed through incubation with biotinylated anti-mouse IgG,
streptavidin-conjugated alkaline phosphatase and finally Vector Red
chromogen substrate (Vector Laboratories, Burlingame, CA). For
confirmation of the veracity of biopsies as fundic mueosa, serial sections
were also stained with monoclonal antibodies against the H/K-ATPase
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(1:5000, the gift of Dr. Adam Smolka, Medical University of South
Carolina, a marker of parietal cells) and gastrin (undiluted, Zymed, a
marker of antral G-cells).
The presence of H. pylori was confirmed in all biopsies with
Giemsa staining. All biopsies demonstrated immunoreactive parietal cells
without the presence of G-cells). In non-infected patients, staining was
confined to normal appearing mucous neck cells_ In Hpylori-infected
patients, nodular aggregates of hSP-staining cells with the characteristics
of Brunner's gland cells (SPEM) were observed in 65 % of biopsies. No
SPEM was observed in fundic biopsies from non-infected patients.
In non-infected patients, fundic biopsies demonstrated only normal
appearing SP-immunoreactive mucous neck cells. In contrast, 65% of
biopsies from H. pylori infected biopsies exhibited aberrant hSP-
immunoreactive SPEM cells. The lineage showed a morphology more
characteristic of Brunner's gland cells. Most cells were present as
nodular formations in the deeper portions of the metaplastic glands.
Foveolar hyperplasia was present in 70% of H. pylori infected biopsies
(Table I). Significant mononuclear infiltrate was present in 95 %o of
biopsies with 18% of the biopsies demonstrating organized lymphoid
aggregates. These results indicated that the SPEM lineage was present in
the fundic mucosa of many patients with H. pylori-associated fundic
gastritis.
Example 2: Association of SPEM with Gastric Adenocarcinomas.
Since chronic H. pylori infection is associated with the
development of adenocarcinoma, archived tissues from resected gastric
adenocarcinomas in patients were examined. All of the resections were
for tumors of the fundus or fundal/antral border.
Ten ~m sections of paraffin-embedded mucosa from regions
adjacent to gross adenocarcinoma were examined for immunostaining with
hSP antibodies as described above. Prominent regions of SPEM were
observed in mucosa underlying regions of foveolar hyperplasia. The
lineage was always observed near the bases of glands. As noted in the
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biopsies, the SPEM cells were large with extensive numbers of
immunoreactive granules. In an adjacent region, hSP staining of normal-
appearing mucous neck cells was observed. Parietal cells were also
observed in these sections. Adjacent sections were stained with anti-PSTI
(1:200) with staining as described above except that sections underwent
retrieval using citrate buffer in a microwave and horseradish peroxidase-
conjugated secondary antibodies were used for detection with
diaminobenzidine chromogen. While distinct PSTI immunoreactive
mucous neck cells were observed within the mucosa, the SPEM lineage
cells at the right side of the section showed no PSTI immunoreactivity.
Adjacent sections were also stained with anti-PS2 (1:50) as described
above. While pS2 immunostainino was observed in regions of surface
cell foveolar hyperplasia, SPEM cells did not stain for pS2. Toluidine
blue staining of a 0.5 ~m section of glutaraldehyde fixed tissue from a
resection specimen demonstrates the numerous granules in SPEM cells.
Note the presence of residual parietal cells in some SPEM-containing
glands, confirming the presence of the lineage in fundic mucosa.
Electron microscopic examination demonstrates the presence of multiple
mucous granules within the SPEM cells along with the characteristic
expanded apical membrane surface without microvilli.
In summary, twenty patients (91 %o) demonstrated the SPEM
lineage within their resection specimens. No evidence of the lineage was
observed in two patients with diffuse infiltrating adenocarcinoma. In
most specimens, a prominent homogeneous cell population expressing hSP
was noted dominating greater than half the lower length of the fundic
glands. These SPEM cells possessed an abundance of cytoplasmic mucin
granules and a wide apical surface. Branching of SPEM-containing
glands was observed in many specimens. Most glands displayed varying
degrees of oxyntic cell atrophy, however there was more variability in
expansion of the surface cell compartment, with 68 % of patients having
foveolar hyperplasia. Normal mucous neck cell staining with hSP and
parietal cells were observed in regions adjacent to SPEM-containing
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regions. Goblet cell-containing intestinal metaplasia was only observed in
10% of specimens.
Resection specimens were stained with several lineage-specific
markers to characterize the origin of the SPEM lineage more completely.
S Increased expression of TGFa has been noted previously in foveolar cells
of patients with Menetrier's disease and hypertrophic lymphocytic gastritis
(Dempsey, et al. Gastroenterology. 103, I9S0-1963 (1992); Bluth, et al.
Hum. Pathol. 26, 1333-1340 (1995)). Ilowever, clear overexpression of
TGFa in the foveolar regions of the mucosa adjacent to tumor was not
observed. In addition, the SPEM lineage did not stain with antibodies
against TGFa. In all cases, there was no evidence of enterochromaffin-
like (ECL) cell hyperplasia, although scattered chromogranin A
immunoreactive cells were observed. The SPEM lineage did not stain
with antibodies against chromogranin A. While antibodies against
1S pancreatic secretory trypsin inhibitor (PSTI) did stain scattered normal
appearing mucous neck cells (McKenzie, et al. Am. J. Physiof. 273,
6112-61117 (1997)), no staining of the lineage was observed. While
antibodies against the trefoil peptide pS2 did stain surface mucous cells in
areas of foveolar hyperplasia, no staining was observed in the SPEM
lineage. Previous investigations have suggested that Intestinal Trefoil
Factor (ITF), which is absent from the normal gastric mucosa, is
unregulated following injury (Podolsky, et al. J. Biol. Chem. 268, 6694-
6702 (1993); Alison, et al. J. Pathol. 175, 405-414 (1995)). While
occasional cells expressing ITF mRNA could be identified in regions of
2S intestinal metaplasia, no ITF expression could be documented in the
SPEM lineage. Finally, examination of SPEM in both thick and thin
plastic sections demonstrated the presence of abundant mucous granules
and a broadened apical surface in these cells. These ultrastructural
characteristics are similar to those of SPEM cells observed in H. telis-
infected CS7BL/6 mice (Wang (1998)). All of these findings indicate that
the SPEM lineage is not directly derived from a normal gastric lineage.
Rather it appears to represent a metaplastic lineage and is differentiable
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from both normal mucous neck cells and the goblet cell-containing type
metaplasia previously associated with chronic H. pylori infection and
atrophic gastritis (Dixon, et al. (1996)).
As noted above, the SPEM lineage was observed in apposition
with both dysplastic lineages as well as adenocarcinoma. hSP staining was
observed in both SPEM as well as in contiguous regions of dysplasia in
49% of resection samples. lmmunoreactivity was detectable in a region
of adenocarcinoma adjacent to the hSP-immunoreactive cells. Ai hieher
magnification, dysplastic epithelial cells appear to be contiguous with
SPEM cell-containing glands. Importantly, however, in 59% of the
resections, hSP immunoreactivity was present in cells within regions of
severe dysplasia or carcinoma in situ. In several cases regions of SP-
expressing dysplastic cells were noted extending from regions of SPEM
lineage. While regions containing the SPEM lineage did not show
significant labelling with Ki-67 and PCNA antibodies, the dysplastic areas
showed prominent nuclear labelling in addition to characteristic changes in
cell morphology. These results indicate that the SPEM lineage may
represent a metaplastic precursor for the development of dysplasia and
adenocarcinoma.
Previous investigations have focused on the association of Type III
intestinal metaplasia with the development of adenocarcinoma_ Despite
this association, it is less clear that neoplastic cells actually arise from
areas in goblet-cell containing intestinal metaplasia. Of note, while
intestinal metaplasia and foveolar hyperplasia are often conspicuous in
atrophic gastritis in association with H. pylori infection, gastric
adenocarcinomas usually develop deep in the glands as nodular lesions
that underlie the regions of intestinal metaplasia or foveolar hyperplasia.
The identification of the SPEM lineage supports the proposal that this
metaplastic candidate precursor is located in proximity with the putative
site of neoplastic transition.
It is not clear whether hSP itself might contribute to the
development of adenocarcinoma. hSP has generally been associated with
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cytoprotection in the gastric mucosa (McKenzie, e't al., ( 1997); Tanaka, et
al. Am. J. Physiol. 272, G 1473-G 1780 ( 1997); Babyatsky, et al.
Gastroenterology. 110, 489-497 (1996)). Homologous deletion of the
gene for the gastric surface cell trefoil protein pS2 leads to the
development of intramucosal carcinomas (Lefebvre, et al. Science 274,
259-262 (1996)) however the lineage responsible for these lesions is
unclear. It is more likely that the expression of SP is a functional marker
of this metaplastic lineage with Brunner's gland morphology. A
metaplasia with Brunner's gland morphology expressing hSP has been
associated with acute and chronic injury of the gastrointestinal mucosae
(Wright, et al. Nature. 343, 82-85 ( 1990); Ahnen, et al. J. Palhol. 173,
a
317-326 ( 1994)) Nevertheless, the ulcer-associated cell lineage (UACL)
appears to constitute a separate entity, since SPEM does not express ITF.
Nevertheless, one can not rule out that SPEM might evolve from UACL
in the gastric mucosa.
The presence of a well differentiated metaplastic lesion as a
precursor of adenocarcinoma is not without precedence. Esophageal
adenocarcinoma develops from dysplastic transition within the metaplastic
columnar Barrett's epithelium in the distal esophagus (Reid, et al.
Gastroenterology. 102, 1212-1219 (1992); Miros, et al. Gut. 32, 1441-
1446 (1991)). As with the SPEM lineage in the stomach, the Barrett's
epithelium shows low proliferative indices. Dysplasia and
adenocarcinoma only develop in a minority (10-15%) of patients. These
studies indicate that, while the SPEM lineage is commonly associated with
fundic H. pylori gastritis, only a minority of patients will progress to
dysplasia and adenocarcinoma. It is therefore likely that further events
must occur to elicit the development of the neoplastic transition. Thus, as
recognition and monitoring of Barrett's epithelium is the mainstay of
surveillance for the development of esophageal adenocarcinoma
(Robertson, et al, M. Br. J. Surg. 75, 760-763 ( 1988)) so surveillance of
patients at risk for gastric adenocarcinoma should focus attention on this
metaplastic precursor lineage expressing SP.
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In summary, these data support the hypothesis that the SFEM
lineage is a link between chronic H. pylori gastritis and dysplasia leading
to gastric adenocarcinoma.
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