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Does α-methylacyl-CoA-racemase play an important role in perineural tumor invasion?
Human Pathology (2007) 38, 1289–1291
www.elsevier.com/locate/humpath
Correspondence
Precursor lesions for uterine leiomyosarcoma To the Editor: I read with interest the recent case report of myometrial dysplasia arising in myometrial hyperplasia [1]. It would be of interest to see a scanning power view of the inframucosal myometrial hyperplasia in the case reported by Cramer et al to more fully evaluate the morphological features of this case. We have recently published a review of 11 uterine leiomyosarcomas in which we looked for possible precursor lesions [2]. We found foci with benign morphological features and increased cellularity in 5 of the cases (resembling the lesion described as myometrial hyperplasia by Cramer et al) and foci resembling symplastic leiomyoma (atypical nuclei without mitoses, similar to the foci of myometrial dysplasia described by Cramer et al) in 2 of these 5 cases. The immunohistochemical features of these areas also differed from the corresponding leiomyosarcomas. These foci could represent areas of myometrial hyperplasia and myometrial dysplasia, respectively, suggesting a possible role for myometrial dysplasia in origins of uterine leiomyosarcoma. Khush Mittal MD New York University School of Medicine New York, NY 10016, USA doi:10.1016/j.humpath.2007.04.018
References [1] Cramer SF, Newcomb PM, Bonfiglio TA. Myometrial dysplasia (atypical myometrial hyperplasia). HUM PATHOL 2007;38:652-5. [2] Mittal K, Joutovsky A. Areas with benign morphologic and immunohistochemical features are associated with some uterine leiomyosarcomas. Gynecol Oncol 2007;104:362-5.
Does a-methylacyl-CoA-racemase play an important role in perineural tumor invasion? To the Editor: Since α-methylacyl-CoA-racemase (AMACR) has been proven to be highly expressed in prostate cancer, the 0046-8177/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
corresponding immunohistochemical marker P504S has become an important tool in the diagnosis of prostate tumors [1]. However, AMACR expression recently has been demonstrated in a variety of other extraprostatic malignancies such as hepatocellular carcinoma, papillary renal cell carcinoma, and colorectal adenocarcinoma [2]. AMACR is known to be a linking enzyme between α- and β-oxidation, thus making metabolic degradation of branched fatty acids possible. Methyl-branched fatty acids and other isoprenoid-derived compounds such as cholesterol and its metabolites must be degraded to prevent their accumulation in the body, which can result in various diseases [3]. The αoxidation cycle yields both (R)- and (S)-isoforms of αmethyl–branched chain compounds, whereas the first enzymes in the β-oxidation cycle are stereospecific for (S)isoforms of their CoA-activated substrates. The necessary stereoisomeric conversion is provided by peroxisomal and mitochondrial AMACR. Peripheral nerve sheaths are composed of complex lipids containing a variety of isoprenoid-derived cholesterol-like substances and long fatty acid compounds such as sphingolipids. Although pathologists have long been aware of the fact that especially prostate cancer has a strong affinity to metastasize to peripheral nerve sheaths, this has never been a target of detailed research. Considering that AMACR represents a central linking enzyme in the metabolism of complex lipids and that such compounds are present in peripheral nerve sheaths, discussion is warranted as to whether tumor cells use this enzyme to degrade nerve sheath substances, thus clearing the way for perineural invasion. Recently, it has been shown that in prostate cancer not only AMACR but also other enzymes in branched fatty acid β-oxidation are upregulated at both the RNA and protein levels, providing further evidence of distinct overactivation of lipid metabolism in this special malignancy [4]. Furthermore, there seems to be a direct interaction between prostatic carcinoma cells and adjacent neuronal tissue, which has been demonstrated in an in vitro model [5]. Aside from prostate cancer, perineural invasion is an often-observed phenomenon especially in pancreatic carcinoma. Immunohistochemistry demonstrates that pancreatic adenocarcinoma, being completely negative for P504S, shows marked expression of AMACR only at the site of
1290
Correspondence
Fig. 1
A, Pancreatic cancer, perineural invasion. Hematoxylin and eosin, ×200. B, Immunostaining for P504S. C, Immunostaining for S100.
perineural invasion (Fig. 1A-C). It is therefore proposed that AMACR might play an important role in perineural tumor invasion. Inasmuch as perineural invasion represents an important pathway for tumor cell spreading, understanding the mechanisms of this phenomenon might provide not only prognostic but even far-reaching therapeutic implications. Further investigation is required. Robin Sen Gupta MD Department of Pathology St.-Agnes-Hospital Bocholt 46397 Bocholt, Germany E-mail addresses: [email protected]; [email protected] doi:10.1016/j.humpath.2007.05.003
References [1] Jiang Z, Woda BA, Wu CL, Yang XJ. Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S). Am J Clin Pathol 2004;34:275-89. [2] Jiang Z, Fanger GR, Woda BA, et al. Expression of alpha-methylacylCoA racemase (P504S) in various malignant neoplasms and normal tissues: a study of 761 cases. HUM PATHOL 2003;34:792-6. [3] Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adultonset sensory motor neuropathy. Nat Genet 2000;24:188-91. [4] Zha S, Ferdinadusse S, Hicks JL, et al. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostatic cancer. Prostate 2005;63:316-23. [5] Ayala GE, Wheeler TM, Shine HD, et al. In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 2001;49:213-23.
Does α-methylacyl-CoA-racemase play an important role in perineural tumor invasion?—reply Dr Gupta brings up an interesting question regarding whether α-methylacyl-CoA racemase (AMACR) plays an important role in perineural tumor invasion.
AMACR, also known as P504S, was identified by the analysis of complementary DNA library subtraction in conjunction with high-throughput microarray screening [1]. In 2001, we described that P504S/AMACR is a new tissue marker for prostate carcinoma [2]. Currently, it has been widely used in clinical practice as a positive marker for the diagnosis of prostate cancer. AMACR, an essential enzyme for the degradation of branched-chain fatty acids by beta oxidation, catalyzes the conversion of several (2R)-methyl branched-chain fatty acylCoAs to their (S)-stereoisomers [3]. As a result, AMACR is a required component of the oxidative metabolism and biosynthetic pathways of branched-chain fatty acids and bile acids, respectively. It is expressed at appreciable levels and is transported to both the peroxisomal and mitochondrial compartments in a variety of tissues [3,4]. Interestingly, we have demonstrated that AMACR is highly up-regulated in premalignant colon adenomas and colon adenocarcinomas but not in normal colon and nonneoplastic hyperplastic polyps [5], whereas epidemiological studies have shown that consumption of red meat and dairy products, which contain large amount of fatty acids, may increase the risk of developing both prostate and colon cancer. Our group also reported that 2 branched-chain fatty acids including pristanic acid and phytanic acid, which are common substrates acted upon by AMACR, markedly increased AMACR protein expression in a prostate cancer cell line (LNCaP cells) but not in a normal prostate basal epithelial cell line (NPrEC cells) [6]. The findings provide a link between the fatty acids and the enhanced expression of AMACR in prostate cancer cells. Based on peripheral nerve sheath containing abundant complex lipids, Gupta suggested that tumor cells may use AMACR to degrade nerve sheath substances. To support this hypothesis, Gupta showed the high expression of AMACR in the pancreatic carcinoma around the nerve, but AMACR was not found in the tumor away from the nerve. Our previous studies support Gupta's hypothesis. Although there are still large gaps between the expression of AMACR and
www.elsevier.com/locate/humpath
Correspondence
Precursor lesions for uterine leiomyosarcoma To the Editor: I read with interest the recent case report of myometrial dysplasia arising in myometrial hyperplasia [1]. It would be of interest to see a scanning power view of the inframucosal myometrial hyperplasia in the case reported by Cramer et al to more fully evaluate the morphological features of this case. We have recently published a review of 11 uterine leiomyosarcomas in which we looked for possible precursor lesions [2]. We found foci with benign morphological features and increased cellularity in 5 of the cases (resembling the lesion described as myometrial hyperplasia by Cramer et al) and foci resembling symplastic leiomyoma (atypical nuclei without mitoses, similar to the foci of myometrial dysplasia described by Cramer et al) in 2 of these 5 cases. The immunohistochemical features of these areas also differed from the corresponding leiomyosarcomas. These foci could represent areas of myometrial hyperplasia and myometrial dysplasia, respectively, suggesting a possible role for myometrial dysplasia in origins of uterine leiomyosarcoma. Khush Mittal MD New York University School of Medicine New York, NY 10016, USA doi:10.1016/j.humpath.2007.04.018
References [1] Cramer SF, Newcomb PM, Bonfiglio TA. Myometrial dysplasia (atypical myometrial hyperplasia). HUM PATHOL 2007;38:652-5. [2] Mittal K, Joutovsky A. Areas with benign morphologic and immunohistochemical features are associated with some uterine leiomyosarcomas. Gynecol Oncol 2007;104:362-5.
Does a-methylacyl-CoA-racemase play an important role in perineural tumor invasion? To the Editor: Since α-methylacyl-CoA-racemase (AMACR) has been proven to be highly expressed in prostate cancer, the 0046-8177/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
corresponding immunohistochemical marker P504S has become an important tool in the diagnosis of prostate tumors [1]. However, AMACR expression recently has been demonstrated in a variety of other extraprostatic malignancies such as hepatocellular carcinoma, papillary renal cell carcinoma, and colorectal adenocarcinoma [2]. AMACR is known to be a linking enzyme between α- and β-oxidation, thus making metabolic degradation of branched fatty acids possible. Methyl-branched fatty acids and other isoprenoid-derived compounds such as cholesterol and its metabolites must be degraded to prevent their accumulation in the body, which can result in various diseases [3]. The αoxidation cycle yields both (R)- and (S)-isoforms of αmethyl–branched chain compounds, whereas the first enzymes in the β-oxidation cycle are stereospecific for (S)isoforms of their CoA-activated substrates. The necessary stereoisomeric conversion is provided by peroxisomal and mitochondrial AMACR. Peripheral nerve sheaths are composed of complex lipids containing a variety of isoprenoid-derived cholesterol-like substances and long fatty acid compounds such as sphingolipids. Although pathologists have long been aware of the fact that especially prostate cancer has a strong affinity to metastasize to peripheral nerve sheaths, this has never been a target of detailed research. Considering that AMACR represents a central linking enzyme in the metabolism of complex lipids and that such compounds are present in peripheral nerve sheaths, discussion is warranted as to whether tumor cells use this enzyme to degrade nerve sheath substances, thus clearing the way for perineural invasion. Recently, it has been shown that in prostate cancer not only AMACR but also other enzymes in branched fatty acid β-oxidation are upregulated at both the RNA and protein levels, providing further evidence of distinct overactivation of lipid metabolism in this special malignancy [4]. Furthermore, there seems to be a direct interaction between prostatic carcinoma cells and adjacent neuronal tissue, which has been demonstrated in an in vitro model [5]. Aside from prostate cancer, perineural invasion is an often-observed phenomenon especially in pancreatic carcinoma. Immunohistochemistry demonstrates that pancreatic adenocarcinoma, being completely negative for P504S, shows marked expression of AMACR only at the site of
1290
Correspondence
Fig. 1
A, Pancreatic cancer, perineural invasion. Hematoxylin and eosin, ×200. B, Immunostaining for P504S. C, Immunostaining for S100.
perineural invasion (Fig. 1A-C). It is therefore proposed that AMACR might play an important role in perineural tumor invasion. Inasmuch as perineural invasion represents an important pathway for tumor cell spreading, understanding the mechanisms of this phenomenon might provide not only prognostic but even far-reaching therapeutic implications. Further investigation is required. Robin Sen Gupta MD Department of Pathology St.-Agnes-Hospital Bocholt 46397 Bocholt, Germany E-mail addresses: [email protected]; [email protected] doi:10.1016/j.humpath.2007.05.003
References [1] Jiang Z, Woda BA, Wu CL, Yang XJ. Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S). Am J Clin Pathol 2004;34:275-89. [2] Jiang Z, Fanger GR, Woda BA, et al. Expression of alpha-methylacylCoA racemase (P504S) in various malignant neoplasms and normal tissues: a study of 761 cases. HUM PATHOL 2003;34:792-6. [3] Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adultonset sensory motor neuropathy. Nat Genet 2000;24:188-91. [4] Zha S, Ferdinadusse S, Hicks JL, et al. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostatic cancer. Prostate 2005;63:316-23. [5] Ayala GE, Wheeler TM, Shine HD, et al. In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 2001;49:213-23.
Does α-methylacyl-CoA-racemase play an important role in perineural tumor invasion?—reply Dr Gupta brings up an interesting question regarding whether α-methylacyl-CoA racemase (AMACR) plays an important role in perineural tumor invasion.
AMACR, also known as P504S, was identified by the analysis of complementary DNA library subtraction in conjunction with high-throughput microarray screening [1]. In 2001, we described that P504S/AMACR is a new tissue marker for prostate carcinoma [2]. Currently, it has been widely used in clinical practice as a positive marker for the diagnosis of prostate cancer. AMACR, an essential enzyme for the degradation of branched-chain fatty acids by beta oxidation, catalyzes the conversion of several (2R)-methyl branched-chain fatty acylCoAs to their (S)-stereoisomers [3]. As a result, AMACR is a required component of the oxidative metabolism and biosynthetic pathways of branched-chain fatty acids and bile acids, respectively. It is expressed at appreciable levels and is transported to both the peroxisomal and mitochondrial compartments in a variety of tissues [3,4]. Interestingly, we have demonstrated that AMACR is highly up-regulated in premalignant colon adenomas and colon adenocarcinomas but not in normal colon and nonneoplastic hyperplastic polyps [5], whereas epidemiological studies have shown that consumption of red meat and dairy products, which contain large amount of fatty acids, may increase the risk of developing both prostate and colon cancer. Our group also reported that 2 branched-chain fatty acids including pristanic acid and phytanic acid, which are common substrates acted upon by AMACR, markedly increased AMACR protein expression in a prostate cancer cell line (LNCaP cells) but not in a normal prostate basal epithelial cell line (NPrEC cells) [6]. The findings provide a link between the fatty acids and the enhanced expression of AMACR in prostate cancer cells. Based on peripheral nerve sheath containing abundant complex lipids, Gupta suggested that tumor cells may use AMACR to degrade nerve sheath substances. To support this hypothesis, Gupta showed the high expression of AMACR in the pancreatic carcinoma around the nerve, but AMACR was not found in the tumor away from the nerve. Our previous studies support Gupta's hypothesis. Although there are still large gaps between the expression of AMACR and