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The Prostate 30:280?281 (1997)
Evaluation and Comparison of Two
New Prostate Carcinoma Markers:
Free-Prostate Specific Antigen and
Prostate Specific
Membrane Antigen
Gerald P. Murphy, Robert J. Barren, Sheila J. Erickson, Victoria A.
Bowes, Robert L. Wolfert, Georg Bartsch, Helmut Klocker, Joseph Pointner,
A. Reissigl, David G. McLeod, Thomas
Douglas, Ted Morgan, Gerald M.
Kenny, Haakon Ragde, Alton L. Boynton, Eric H. Holmes
From the Pacific Northwest Cancer Foundation, Cancer Research Division, Northwest Hospital, Seattle,
Washington [G.P.M., R.J.B., S.J.E.,
V.A.B., G.M.K., H.R., A.L.B., E.H.H.];
Hybritech, Incorporated, Division of
Diagnostics Research and Development, San Diego, California [R.L.W.];
Department of Urology, University of
Innsbruck, Innsbruck, Austria [G.B.,
H.K., J.P., A.R.]; Urology Service, Walter Reed Army Medical Center, Washington, DC [D.G.M., T.D., T.M.]; Uniformed Services University for Health
Sciences, Bethesda, Maryland [D.G.M.,
T.D., T.M.]; Center for Prostate Disease
Research, Washington, DC [D.G.M.].
Cancer 78:809?818, 1996.
BACKGROUND. Two new prostate cancer markers, free-prostate specific antigen (f-PSA) and prostate specific membrane antigen (PSMA) were
recently introduced. This report summarizes a prospective two-year multicenter test of their diagnostic or prognostic capabilities. Total PSA was also
METHODS. There were four
clinical groups studied: (1) 226 individuals from a screening project undergoing ultrasound and biopsy evaluation had markers obtained: (2) 68 patients suspected of having prostate
cancer and undergoing 2 or more biopsies had the markers obtained on multiple occasions: (3) 100 patients undergoing radical prostatectomy had markers obtained pre- and post-operatively:
and (4) 31 patients with metastatic
prostate cancer each had multiple
samples for marker assay obtained over
a 2-year period. In all, 465 patients had
one or more samples obtained and studied.
RESULTS. Free-PSA affords little
additional diagnostic advantage compared with total PSA in the screening
population. The receiver operating
characteristic curves for diagnostic accuracy were ranked: (1) PSA density;
(2) total PSA; (3) f-PSA; and (4) PSMA.
PSMA showed the best correlation
with stage of the primary tumor in the
screened group. In the multiple negative biopsy group, f-PSA varied from
12 to 21%. PSMA values were evaluated in all histologic categories. PSA
density was �15 in all categories. In
the prostatectomy cases PSA values
postoperatively were quite low in
Stage II; f-PSA was of no value. Later,
f-PSA was increased in association
with elevated total PSA values. Mean
PSMA values were above normal in all
postoperative time periods except in
Stage III patients at 6 months to 1 year
postoperatively. PSA densities were all
�15. In patients with metastatic carcinoma, elevated PSMA values correlated best with a poor prognosis (clinical progression), as has been described.
CONCLUSIONS. These data suggest that f-PSA values do not provide
additional diagnostic benefit compared
with total PSA in screening populations, in the presence of suspected cancer, postprostatectomy, or in metastatic
disease. PSMA is of prognostic significance, especially in the presence of
metastatic disease, and correlates well
with the stage of disease in cancers detected in a screened population.
� 1996 American Cancer Society. (Reproduced with permission of Wiley-Liss, Inc.,
a subsidiary of John Wiley & Sons, Inc.)
Near Tetraploid Prostate
Carcinoma: Methodologic and
Prognostic Aspects
Gun Forsslund, Bo Nilsson,
Anders Zetterberg
From the Department of Oncology-Pathology, Unit of Tumor Pathology, Karolinska Institute, Stockholm,
Sweden [G.F., A.Z.]; Department of
Cancer Epidemiology, The Karolinska
Hospital, Stockholm, Sweden [B.N.].
Cancer 78:1748?1755, 1996.
BACKGROUND. The clinical
value of DNA ploidy analysis in prostate carcinoma has been an issue for
investigation for more than 2 decades.
In general, diploid or pseudodiploid
tumors are associated with a favorable
prognosis and aneuploid tumors with
an unfavorable prognosis, irrespective
of type of treatment. Tumors with
DNA values in the tetraploid region
(around 4c) present a diagnostic problem. Such DNA distributions may
clearly represent aneuploid tumors
with an unfavorable prognosis. However, a 4c distribution may conversely
represent a tetraploid tumor (possibly
a polyploid variant of the diploid tumor) with a favorable prognosis. Previous data from our laboratory indicate
the existence of such a tetraploid subgroup. The goal of the current study
was to investigate the diagnostic problem of 4c tumors in greater detail.
METHODS. Ploidy classification
of cytologic smears by image cytometry was performed in a retrospective
study of 334 patients with hormonally
treated prostate carcinoma. Follow-up
time was 30 years or until death.
RESULTS. Three ploidy types
were defined: near-diploid (D type),
near-tetraploid (T type), and highly aneuploid (A type). Tumors with a modal
value within the tetraploid region were
found in 27% (92 cases) of the total material. Of these, 9% were defined as T
type and 18% as A type. Overall, 37%
of the tumors were classified as D type,
9% as T type, and 54% as A type. Of the
A type tumors, one-third had modal
DNA values in the tetraploid (4c) region. Multivariate analysis showed a
statistically significant difference between A type tumors and D and T
type, but not between D type and T
type. Both D and T type tumors progressed slowly and killed the patients 5
to 30 years after diagnosis, whereas A
type tumors progressed rapidly and
killed the patients within 6 years of diagnosis.
CONCLUSIONS. By image cytometry, prostate carcinoma can be divided into three ploidy types:
D, T, and A type. Biologically,
however, the tumors fall into only two
groups: low grade malignant, pseudodiploid tumors of D or T type, and high
grade malignant, highly aneuploid tumors of A type. � 1996 American Cancer
Society. (Reproduced with permission of
Wiley-Liss, Inc., a subsidiary of John Wiley
& Sons, Inc.)
Progression of Prostatic
Intraepithelial Neoplasia to Invasive
Carcinoma in C3(1)/SV40 Large T
Antigen Transgenic Mice:
Histopathological and Molecular
Biological Alterations
Masa-Aki Shibata, Jerrold M.
Ward, Deborah E. Devor, Min-Ling
Liu, and Jeffrey E. Green
From the Veterinary and
Tumor Pathology Section, Office
of Laboratory Animal Science [M-A.S.,
J.M.W., D.E.D.]; Laboratory of Molecular Oncology [M-A.S., M-L.L., J.E.G.];
Division of Basic Science, National
Cancer Institute, Frederick, Maryland
Cancer Res 56:4894?4903, 1996.
The progression of prostatic intraepithelial neoplasia (PIN) to invasive
prostate carcinoma has been analyzed
in the C3(1)/TAG transgenic mouse
model and appears very similar to the
process proposed to occur in humans.
PIN lesions in these transgenic mice
histologically resemble those found in
human PIN. Low-grade PIN was observed in the ventral and dorsolateral
lobes at 2 months of age, whereas highgrade PIN was found in both lobes by
5 months of age. A progressive increase in the number of PIN lesions
was observed with age. Prostate carcinomas, which appeared to arise from
PIN lesions, were found by 7 months of
age in the ventral lobe and 11 months
of age in the dorsolateral lobe. Expression of TAG mRNA and protein in these
lesions correlated with the development of PIN and carcinomas, as did the
overexpression of p53 protein. Apoptosis levels were quite low in normal ep-
ithelial cells, moderate in low-grade
PIN, and high in high-grade PIN and
carcinomas. Levels of expression of
proliferating cell nuclear antigen correlated with the degree of severity of the
prostate lesions. Eighteen % of PIN lesions were found to already harbor Haras mutations, whereas 33% of carcinomas showed various mutations in Haras, Ki-ras, and/or p53. Mutations in
Ha-ras may, therefore, be an early
event in a significant portion of PIN
lesions. Because high-grade PIN
showed many characteristics similar to
those observed in carcinomas and
high-grade PIN was often found contiguous to carcinomas, we conclude
that high-grade PIN is a precursor lesion of prostate carcinoma in this transgenic model. These transgenic mice
will be useful to study mechanisms responsible for the progression of invasive
carcinomas from PIN precursor lesions,
as may occur during the development of
prostate cancer in humans. (Reproduced
with permission of the American Association
for Cancer Research, Inc.)
Focal Adhesion Kinase (pp125FAK)
Expression, Activation and
Association with Paxillin and
p50CSK in Human Metastatic
Prostate Carcinoma
Lise Tremblay, Wendy Hauck,
Armen G. Aprikian, Louis R. Begin,
Alcide Chapdelaine and Simone
From the Departments of Surgery
(Urology) and Pathology, McGill University [A.G.A., S.C.]; The Montreal
General Hospital Research Institute
[L.T., W.H., S.C.]; The Jewish General
Hospital [L.R.B.]; Departments of
Medicine and Biochemistry, University
of Montreal and The Maisonneuve-
Rosemont Hospital Research Center,
Montreal, Canada [A.C., S.C.]
Int J Cancer 68:164?171, 1996.
pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins
in focal adhesion plaques, is known to
transduce signals involved in the regulation of cell adhesion and motility as
well as the anchorage-independent
growth of transformed cells. We investigated whether pp125FAK could be
part of a signalling pathway that contributes to the progression of human
prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine
and its association with paxillin and
p50csk were preferentially observed in
PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues
showed undetectable or low levels of
both FAK mRNA and protein and an
absence of pp125FAK signalling complexes. The increase in expression and
activation of pp125FAK in metastatic
PCa tissues was also corroborated by
our findings in human PCa cell lines.
Indeed, higher levels of pp125FAK and
FAK mRNA were observed in highly
tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed
to an inactive form in LNCaP cells,
which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin
and p50csk in PC-3 cells as in metastatic
PCa tissues. Together, our results show
that an increase in FAK mRNA and
protein, as well as pp125FAK activation
and association with signalling proteins, correlates with progression and
invasion in human PCa tissues and
� 1996 Wiley-Liss Inc. (Reproduced with
permission of Wiley-Liss, Inc., a subsidiary
of John Wiley & Sons, Inc.)
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