CONTEXT: 5-Lipoxygenase (5-LO) is an arachidonic acid- metabolizing enzyme, which has been demonstrated to exert a role in colorectal cancer tumorigenesis. Its activity in promoting neoangiogenesis in colorectal malignancies has been also recently theorized on the basis of in vitro studies. OBJECTIVE: To investigate whether any correlation existed between 5-LO immunoexpression amount and the quantity of neoangiogenesis, as reflected by microvessel density (MVD) in human sporadic surgically resected colorectal adenocarcinomas. DESIGN: A total of 45 formalin-fixed, paraffin-embedded colorectal adenocarcinomas were submitted to the immunohistochemical procedures for 5-LO and CD105, which represent specific markers for neoangiogenesis and which were used in the assessment of MVD. RESULTS: CD105-positive, intratumoral, newly formed vessels were present in 45 of 45 cases with variable MVD values. A 5-LO-positive immunohistochemical reaction was also found in 45 of 45 cases. A significantly higher MVD was evident in cases displaying a high 5-LO amount in comparison with those characterized by a low 5-LO expression (28.33 vs 19.44 vessels per mm(2); P = .02). In addition, a positive significant correlation emerged between 5-LO immunoexpression amount and the MVD counts (r = 0.2986, P = .04). CONCLUSIONS: Our study demonstrates the existence of a relationship between 5-LO expression and the neoangiogenesis process as reflected by intratumoral MVD in human sporadic colorectal adenocarcinomas, thus suggesting that 5-LO may modulate the formation of blood vessels in these neoplasias.
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: email@example.com). 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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