Correlative Study of Microvessel Density and 5-Lipoxygenase Expression in Human Sporadic Colorectal Cancer by ProQuest


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									              Correlative Study of Microvessel Density and
             5-Lipoxygenase Expression in Human Sporadic
                            Colorectal Cancer
                       Valeria Barresi, MD; Enrica Vitarelli, Bbs; Giovanni Tuccari, MD; Gaetano Barresi, MD

● Context.—5-Lipoxygenase (5-LO) is an arachidonic acid–                  vessels were present in 45 of 45 cases with variable MVD
metabolizing enzyme, which has been demonstrated to ex-                   values. A 5-LO–positive immunohistochemical reaction
ert a role in colorectal cancer tumorigenesis. Its activity in            was also found in 45 of 45 cases. A significantly higher
promoting neoangiogenesis in colorectal malignancies has                  MVD was evident in cases displaying a high 5-LO amount
been also recently theorized on the basis of in vitro studies.            in comparison with those characterized by a low 5-LO ex-
   Objective.—To investigate whether any correlation ex-                  pression (28.33 vs 19.44 vessels per mm2; P       .02). In
isted between 5-LO immunoexpression amount and the                        addition, a positive significant correlation emerged be-
quantity of neoangiogenesis, as reflected by microvessel                   tween 5-LO immunoexpression amount and the MVD
density (MVD) in human sporadic surgically resected co-                   counts (r    0.2986, P   .04).
lorectal adenocarcinomas.                                                    Conclusions.—Our study demonstrates the existence of
   Design.—A total of 45 formalin-fixed, paraffin-embed-                    a relationship between 5-LO expression and the neoangi-
ded colorectal adenocarcinomas were submitted to the im-                  ogenesis process as reflected by intratumoral MVD in hu-
munohistochemical procedures for 5-LO and CD105,                          man sporadic colorectal adenocarcinomas, thus suggesting
which represent specific markers for neoangiogenesis and                   that 5-LO may modulate the formation of blood vessels in
which were used in the assessment of MVD.                                 these neoplasias.
   Results.—CD105-positive, intratumoral, newly formed                       (Arch Pathol Lab Med. 2008;132:1807–1812)

A   rachidonic acid, a fatty acid mainly derived from di-
      etary sources, is metabolized by 3 major pathways:
(1) the cyclooxygenase pathway, which leads to the for-
                                                                          cells or tissues in comparison with the corresponding nor-
                                                                          mal colonic cells or epithelium,14–17 thus suggesting
                                                                          5-LO’s role in colorectal tumorigenesis. The hypothesis,
mation of prostaglandins (PGs); (2) the lipoxygenase (LO)                 according to which 5-LO contributes to colorectal carci-
pathway, which forms hydroperoxyeicosatetraenoic acids,                   nogenesis, has been further confirmed by the reduction of
hydroxyeicosatetraenoic acids, and leukotrienes; and (3)                  tumor growth obtained as a result of the use of 5-LO–
the cytochrome P-450 monooxygenase pathway, which                         specific inhibitors in in vitro cigarette smoke–induced co-
leads to the formation of epoxydes.1                                      lorectal cancer.17 Besides the protumorigenic action, a
   Three major LOs have been characterized in human tis-                  proangiogenic role has been proposed for 5-LO in colo-
sues. They have been named 5-LO, 12-LO, and 15-LO for                     rectal malignancies. Indeed, in vitro studies on cigarette
their ability to insert molecular oxygen at the 5, 12, or 15              smoke–induced colon cancer have also shown the effective
carbon atom of arachidonic acid. These enzymes have                       inhibition of tumor angiogenesis as a consequence of
been demonstrated to exert a protumorigenic role in hu-                   5-LO selective suppression.17
man neoplasias. Indeed, the significant elevation of their                    In the present study, we investigated the possible corre-
metabolites has been evidenced in several malignancies,                   lations between 5-LO expression amount and tumor neoan-
in accordance with their role in tumor growth, progres-                   giogenesis in a series of human sporadic surgically resected
sion, and angiogenesis2–4 and their involvement in various                colorectal adenocarcinomas. In particular, our purpose was
steps of carcinogenesis.5,6                                               to verify whether any difference in the quantity of neoan-
   The 5-LO involvement in cancer pathobiology is indi-                   giogenesis was present between cases with a low and a high
cated by its overexpression, together with one of its ter-                5-LO expression, consistent with the hypothesis that angio-
minal products, LTB4, in a broad variety of cancer cells4,6–9             genesis is mediated through the increase in 5-LO expression
and human cancer tissues.10–13 Specifically, higher 5-LO                   in colorectal cancer. Indeed, if confirmed, this assumption
amounts have been detected in human colorectal cancer                     might open new perspectives in the therapy of this neopla-
                                                                          sia, with the 5-LO–immunoexpressing colorectal carcinomas
                                                                          eventually treated with both antiangiogenic drugs and 5-
   Accepted for publication April 3, 2008.                                LO–specific inhibitors.
   From the Department of Human Pathology, University of Messina,
Messina, Italy.                                                                          MATERIALS AND METHODS
   The authors have no relevant financial interest in the products or
companies described in this article.                                        A total of 45 nonconsecutive surgical cases of colorectal ade-
   Reprints: Valeria Barresi, MD, Department of Human Pathology, Pol-     nocarcinomas obtained from the same number of patients (19
iclinico Univeristario G. Martino, Pad D – Via Consolare Valeria, 98125   females [42%] and 26 males [58%]; age range, 36–89 years; mean
Messina, Italy (e-mail:                      age, 68.2 years) were selected from the files of the Department
Arch Pathol Lab Med—Vol 132, November 2008                                      5-LO and MVD in Colorectal Carcinoma—Barresi et al   1807
of Human Pathology of the University of Messina, Italy. Selection      called hot spots) under a 40 field. Microvessels were then
was based on clinical records, so that patients who had received       counted in each of these areas under a 400 field. Only those
preoperative neoadjuvant t
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