Migrating with Myosin VI
2006; Elsevier BV; Volume: 169; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2006.060712
ISSN1525-2191
Autores Tópico(s)RNA Research and Splicing
ResumoOne reason to embark in the analysis of global gene expression differences between normal and cancerous prostate epithelial cells is to determine mechanisms that are responsible for prostate cancer development. In this issue of The American Journal of Pathology, Dunn et al1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar identify myosin VI as a gene that is consistently overexpressed in prostate cancer compared with normal epithelium. Previous studies of myosin VI have revealed overexpression in ovarian cancer and a role of myosin VI in cell migration, endocytosis, and cell polarity.2Cheng KW Lahad JP Kuo WL Lapuk A Yamada K Auersperg N Liu J Smith-McCune K Lu KH Fishman D Gray JW Mills GB The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers.Nat Med. 2004; 10: 1251-1256Crossref PubMed Scopus (413) Google Scholar, 3Buss F Luzio JP Kendrick-Jones J Myosin VI, an actin motor for membrane traffic and cell migration.Traffic. 2002; 3: 851-858Crossref PubMed Scopus (69) Google Scholar, 4Hasson T Myosin VI: two distinct roles in endocytosis.J Cell Sci. 2003; 116: 3453-3461Crossref PubMed Scopus (141) Google Scholar In addition to these cellular processes, which can all be linked to oncogenesis, the study by Dunn et al1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar identifies a novel function of myosin VI. They demonstrate that a sharp decrease in myosin VI expression causes global gene expression changes and reduces the ability of prostate cancer cells to grow as colonies in soft agar. Based on this new insight about the role of myosin VI in prostate cancer, we examine here the broader function of myosin VI during prostate cancer development and cancer cell invasion.Myosin VI Is an Early Marker of Prostate Cancer DevelopmentThe first clue that myosin VI may indeed be an early target of oncogenic transformation in prostate cancer development is the observation that myosin VI is overexpressed in proliferative inflammatory atrophy (PIA)5De Marzo AM Marchi VL Epstein JI Nelson WG Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis.Am J Pathol. 1999; 155: 1985-1992Abstract Full Text Full Text PDF PubMed Scopus (721) Google Scholar and in prostatic intraepithelial neoplasia (PIN).1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar PIN possesses the histopathological features of cancer and is generally recognized as a precursor for invasive carcinoma, but the molecular requirements for progression of PIN to invasive cancer have been difficult to determine. Because myosin VI is uniformly expressed in individual PIN lesions, it is not sufficient for invasion. However, myosin VI expression in PIN strongly suggests that it takes an active role or is at least linked to the selection process of PIN cells that become invasive. Anecdotal evidence supports the concept that invasive cells proliferate slowly,6Klezovitch O Chevillet J Mirosevich J Roberts RL Matusik RJ Vasioukhin V Hepsin promotes prostate cancer progression and metastasis.Cancer Cell. 2004; 6: 185-195Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar and a recent molecular study identifies pathways that are responsible for the reciprocal switches from cell migration and invasion to cell proliferation that may be operational in the progression of PIN to invasive cancer.7Gao CF Xie Q Su YL Koeman J Khoo SK Gustafson M Knudsen BS Hay R Shinomiya N Vande Woude GF Proliferation and invasion: plasticity in tumor cells.Proc Natl Acad Sci USA. 2005; 102: 10528-10533Crossref PubMed Scopus (138) Google Scholar Because myosin VI overexpression increases cell migration, myosin VI most likely facilitates the invasion of PIN cells into the stroma.As demonstrated by Dunn et al,1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar myosin VI is already expressed in the precursor lesion of PIN or PIA. This histological entity is not considered malignant but may be a precursor of malignancy because it is commonly associated with PIN and invasive cancer.8Putzi MJ De Marzo AM Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia.Urology. 2000; 56: 828-832Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Several cancerous molecular changes are detectable in PIA, including hypermethylation of glutathione S-transferase-pi, gain of chromosome 8, and expression of the cell cycle-dependent kinase inhibitor p16.9De Marzo AM DeWeese TL Platz EA Meeker AK Nakayama M Epstein JI Isaacs WB Nelson WG Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment.J Cell Biochem. 2004; 91: 459-477Crossref PubMed Scopus (159) Google Scholar In addition, there is high expression of proteins associated with a stress response, such as cyclooxygenase-210Zha S Gage WR Sauvageot J Saria EA Putzi MJ Ewing CM Faith DA Nelson WG De Marzo AM Isaacs WB Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma.Cancer Res. 2001; 61: 8617-8623PubMed Google Scholar and glutathione-S-transferase A1.11Parsons JK Nelson CP Gage WR Nelson WG Kensler TW De Marzo AM GSTA1 expression in normal, preneoplastic, and neoplastic human prostate tissue.Prostate. 2001; 49: 30-37Crossref PubMed Scopus (82) Google Scholar The expression of myosin VI protein in PIA may be associated with a stress response as well, in particular cell stress in response to DNA damage. In this context, the transcriptional activation of the myosin VI gene may occur through a p53-dependent mechanism on activation of p53 in response to DNA damage.12Jung EJ Liu G Zhou W Chen X Myosin VI is a mediator of the p53-dependent cell survival pathway.Mol Cell Biol. 2006; 26: 2175-2186Crossref PubMed Scopus (59) Google Scholar Because the functional integrity of p53 is probably preserved in PIN cells and only lost later in cancer progression, p53 can induce myosin VI gene transcription in PIN. Thus, myosin VI overexpression occurs before cells become overtly malignant. It appears that overexpression of myosin VI is tolerated during cancer development as cells acquire additional genetic changes. It is likely that some genetic alterations in cancer cells will interact with myosin VI and that the function of myosin VI changes during the development of PIN and the progression to invasive cancer.Myosin VI and Prostate Cancer InvasionLocally invasive prostate cancers possess a unique architecture by forming a highly branched ductal network. This histological growth pattern strongly suggests the deregulation of branching morphogenesis and the classic microscopic description of prostate cancer as "small glands, back-to-back" results from the two-dimensional view of an excessively branched three-dimensional ductal tree. The growth of prostate cancer relies on cell motility and proteolysis at the tips of ducts, in locations of stromal invasion.13Davies JA Watching tubules glow and branch.Curr Opin Genet Dev. 2005; 15: 364-370Crossref PubMed Scopus (17) Google Scholar The three-dimensional process of branching morphogenesis by prostate cancer cells is difficult to recapitulate in vitro. A major driving force is the prostate stroma, with malignant epithelial cells inappropriately responding to stromal stimuli. Thus, the excessive branching morphogenesis relies largely on aberrant reciprocal interactions between stroma and epithelium. There is a possibility that the overexpression of myosin VI alters the response of epithelial cells to stromal stimuli. There are two subcellular compartments, the endocytic compartment and the leading edge of migratory cells that contain myosin VI. They are both involved in the regulation of cell migration in response to growth factor stimulation.4Hasson T Myosin VI: two distinct roles in endocytosis.J Cell Sci. 2003; 116: 3453-3461Crossref PubMed Scopus (141) Google Scholar, 14Buss F Luzio JP Kendrick-Jones J Myosin VI, a new force in clathrin mediated endocytosis.FEBS Lett. 2001; 508: 295-299Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 15Aschenbrenner L Naccache SN Hasson T Uncoated endocytic vesicles require the unconventional myosin, Myo6, for rapid transport through actin barriers.Mol Biol Cell. 2004; 15: 2253-2263Crossref PubMed Scopus (96) Google Scholar, 16Buss F Arden SD Lindsay M Luzio JP Kendrick-Jones J Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis.EMBO J. 2001; 20: 3676-3684Crossref PubMed Scopus (229) Google Scholar Thus, an increased expression of myosin VI could enhance the response of cells to stromal factors and facilitate tumor invasion.Defects in endocytosis trigger cell proliferation, and a regulator of endocytosis, Rab25, is up-regulated in breast and ovarian cancer.2Cheng KW Lahad JP Kuo WL Lapuk A Yamada K Auersperg N Liu J Smith-McCune K Lu KH Fishman D Gray JW Mills GB The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers.Nat Med. 2004; 10: 1251-1256Crossref PubMed Scopus (413) Google Scholar Overexpression of myosin VI might constitute an alternative pro-oncogenic mechanism for altering endocytosis. Myosin VI associates with endocytic vesicles through the tumor suppressor protein disabled 2 (Dab2).3Buss F Luzio JP Kendrick-Jones J Myosin VI, an actin motor for membrane traffic and cell migration.Traffic. 2002; 3: 851-858Crossref PubMed Scopus (69) Google Scholar, 16Buss F Arden SD Lindsay M Luzio JP Kendrick-Jones J Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis.EMBO J. 2001; 20: 3676-3684Crossref PubMed Scopus (229) Google Scholar, 17Morris SM Arden SD Roberts RC Kendrick-Jones J Cooper JA Luzio JP Buss F Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton.Traffic. 2002; 3: 331-341Crossref PubMed Scopus (198) Google Scholar, 18Inoue A Sato O Homma K Ikebe M DOC-2/DAB2 is the binding partner of myosin VI.Biochem Biophys Res Commun. 2002; 292: 300-307Crossref PubMed Scopus (58) Google Scholar Dab2 expression is frequently lost in human cancer, and Dab2 heterozygous mice develop hyperplasia and dysplasia of the ovarian surface epithelium.19Yang DH Fazili Z Smith ER Cai KQ Klein-Szanto A Cohen C Horowitz IR Xu XX Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53-null background.Am J Pathol. 2006; 169: 258-267Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Dab2 binds to the Dab2-interacting protein (Dab2IP), which has potent growth inhibitory activity and which is lost by methylation in different cancer types, including prostate cancer.20Chen H Toyooka S Gazdar AF Hsieh JT Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines.J Biol Chem. 2003; 278: 3121-3130Crossref PubMed Scopus (119) Google Scholar Therefore, prostate cancer cells potentially overexpress the pro-oncogenic protein myosin VI under conditions in which expression of tumor suppressor proteins Dab2 and Dab2IP are decreased. Because Dab2 mediates the association of myosin VI with endosomes,4Hasson T Myosin VI: two distinct roles in endocytosis.J Cell Sci. 2003; 116: 3453-3461Crossref PubMed Scopus (141) Google Scholar loss of Dab2 prevents myosin VI association with endosomes, and this might increase the concentration of myosin VI in other subcellular compartments. For example, an increase of myosin VI in membrane ruffles at the leading edge of cells would facilitate cell migration. Theoretically, it should be possible to examine changes in subcellular localization of myosin VI in vivo in immunohistochemical staining images. However, immunohistochemical results show diffuse localization of myosin VI throughout the cytoplasm, because myosin VI also associates with the Golgi complex21Buss F Kendrick-Jones J Lionne C Knight AE Cote GP Paul Luzio J The localization of myosin VI at the golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles of A431 cells after growth factor stimulation.J Cell Biol. 1998; 143: 1535-1545Crossref PubMed Scopus (167) Google Scholar and secretory vesicles.21Buss F Kendrick-Jones J Lionne C Knight AE Cote GP Paul Luzio J The localization of myosin VI at the golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles of A431 cells after growth factor stimulation.J Cell Biol. 1998; 143: 1535-1545Crossref PubMed Scopus (167) Google Scholar, 22Warner CL Stewart A Luzio JP Steel KP Libby RT Kendrick-Jones J Buss F Loss of myosin VI reduces secretion and the size of the Golgi in fibroblasts from Snell's waltzer mice.EMBO J. 2003; 22: 569-579Crossref PubMed Scopus (117) Google Scholar It is therefore not possible to measure the amount of myosin VI in the apical compartment of cancer cells, where endocytosis occurs, or at the surface of cancer cells at the invasive front. More quantitative methods are necessary to demonstrate changes in subcellular localization of myosin VI in vivo and to determine whether myosin VI concentrations differ in subcellular compartments of benign and malignant prostate epithelial cells.The overexpression of myosin VI protein potentially augments cell motility at discrete stages of cancer progression. In the initial stages of cancer development, cell motility increases with the acquisition of an invasive phenotype at the transition from PIN to invasive carcinoma. During disease progression, cell motility plays a critical role in the systemic dissemination of cancer cells. It is uncertain, whether the same molecular mechanisms trigger cell movement at different times during prostate oncogenesis and metastasis. The function of myosin VI in epithelial cell migration has been studied in D. melanogaster.23Geisbrecht ER Montell DJ Myosin VI is required for E-cadherin-mediated border cell migration.Nat Cell Biol. 2002; 4: 616-620Crossref PubMed Scopus (184) Google Scholar In fly ovaries, the egg chamber is surrounded by a simple epithelium. During oogenesis, a cluster of distinct follicle cells forms at the anterior pole.24Montell DJ Command and control: regulatory pathways controlling invasive behavior of the border cells.Mech Dev. 2001; 105: 19-25Crossref PubMed Scopus (48) Google Scholar Myosin VI is highly expressed in follicle cells, and expression is maintained when a small subgroup of follicle cells, called border cells, delaminates from the epithelium and migrates between nurse cells toward the oocyte.25Montell DJ Border-cell migration: the race is on.Nat Rev Mol Cell Biol. 2003; 4: 13-24Crossref PubMed Scopus (241) Google Scholar This process is reminiscent of tumor cell invasion. Initially, the border cells are polarized epithelial cells with cell-cell junctions that consist of distinct membrane subdomains. For migration, the cell polarity changes from apical to planar, proteins from cell-cell junctions reorganize at the invasive edge of the cell to facilitate cell motility and invasion,26Pinheiro EM Montell DJ Requirement for Par-6 and Bazooka in Drosophila border cell migration.Development. 2004; 131: 5243-5251Crossref PubMed Scopus (98) Google Scholar and myosin VI translocates from cell-cell junctions to membrane ruffles at the invasive front of the cells. The correct localization of proteins at tight junctions that maintain cell polarity depends on expression of myosin VI.26Pinheiro EM Montell DJ Requirement for Par-6 and Bazooka in Drosophila border cell migration.Development. 2004; 131: 5243-5251Crossref PubMed Scopus (98) Google Scholar In migratory border cells, migration is significantly impaired in the absence of myosin VI. Similar to observations in border cells, myosin VI knockdown in LNCaP cells slows cell migration.1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar These results demonstrate that myosin VI promotes cell migration in vitro and may cause tumor invasion in vivo. It will be interesting to examine whether the increase in cell migration follows a disorganization of cell-cell junctions and a loss of cell polarity.Unanswered QuestionsMyosin VI joins a group of genes that are overexpressed in cancer and that can stimulate the motility and invasion of prostate cancer cells. Other genes that belong in this functional category are the cell surface protease hepsin,27Luo J Duggan DJ Chen Y Sauvageot J Ewing CM Bittner ML Trent JM Isaacs WB Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling.Cancer Res. 2001; 61: 4683-4688PubMed Google Scholar, 28Magee JA Araki T Patil S Ehrig T True L Humphrey PA Catalona WJ Watson MA Milbrandt J Expression profiling reveals hepsin overexpression in prostate cancer.Cancer Res. 2001; 61: 5692-5696PubMed Google Scholar, 29Welsh JB Sapinoso LM Su AI Kern SG Wang-Rodriguez J Moskaluk CA Frierson Jr, HF Hampton GM Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.Cancer Res. 2001; 61: 5974-5978PubMed Google Scholar, 30Dhanasekaran SM Barrette TR Ghosh D Shah R Varambally S Kurachi K Pienta KJ Rubin MA Chinnaiyan AM Delineation of prognostic biomarkers in prostate cancer.Nature. 2001; 412: 822-826Crossref PubMed Scopus (1424) Google Scholar Trefoil factor 3,31Faith DA Isaacs WB Morgan JD Fedor HL Hicks JL Mangold LA Walsh PC Partin AW Platz EA Luo J De Marzo AM Trefoil factor 3 overexpression in prostatic carcinoma: prognostic importance using tissue microarrays.Prostate. 2004; 61: 215-227Crossref PubMed Scopus (69) Google Scholar, 32Garraway IP Seligson D Said J Horvath S Reiter RE Trefoil factor 3 is overexpressed in human prostate cancer.Prostate. 2004; 61: 209-214Crossref PubMed Scopus (50) Google Scholar genes involved in polyamine biosynthesis,33Rhodes DR Barrette TR Rubin MA Ghosh D Chinnaiyan AM Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer.Cancer Res. 2002; 62: 4427-4433PubMed Google Scholar and neuropilin-1.34Lapointe J Li C Higgins JP van de Rijn M Bair E Montgomery K Ferrari M Egevad L Rayford W Bergerheim U Ekman P DeMarzo AM Tibshirani R Botstein D Brown PO Brooks JD Pollack JR Gene expression profiling identifies clinically relevant subtypes of prostate cancer.Proc Natl Acad Sci USA. 2004; 101: 811-816Crossref PubMed Scopus (1046) Google Scholar Because myosin VI is expressed in precancerous lesions of proliferative inflammatory atrophy,1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar it most likely affects cell motility early during cancer development. Although we have learned from array studies that the expression of several genes that stimulate cell migration increases when cells become cancerous, it is not clear how these genes interact to trigger invasion of prostate cancer cells, whether they are activated in a stepwise process during cancer cell invasion and metastasis, whether they are co-expressed in the same cancer cells, or whether they function in separate clonal cell populations. With the exception of hepsin,6Klezovitch O Chevillet J Mirosevich J Roberts RL Matusik RJ Vasioukhin V Hepsin promotes prostate cancer progression and metastasis.Cancer Cell. 2004; 6: 185-195Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar the migration-stimulating activities of genes that are identified in array experiments have only been tested in cell line experiments. These in vitro experiments are unable to capture a gene's migration-inducing function, which requires an organismal context. If the induction of cell migration depends on cell-cell interactions, an organotypic in vitro system is needed. Specific to prostate epithelium, three-dimensional organotypic cultures have been difficult to establish in a reproducible fashion, and thus, molecular mechanisms of cell migration and invasion that rely on epithelial and stromal cross-talk are poorly characterized. Therefore, to further investigate the function of myosin VI in prostate cancer development requires an animal model. This is particularly critical in analyzing the role of myosin VI in branching morphogenesis of normal and cancerous prostatic ducts.It is apparent that myosin VI overexpression can promote oncogenesis by a variety of mechanisms, and future studies are necessary to determine which of these mechanisms operate during the development of prostate cancer. The connection between myosin VI overexpression in the endocytic compartment and the stimulation of oncogenesis also requires additional investigation. It is conceivable that the link between the endocytic compartment and cellular proliferation and migration is through regulation of epithelial polarity. More research is needed to determine whether these compartments are connected through myosin VI or whether myosin VI assumes separate roles in regulating endocytosis, cell polarity, and cell migration. Finally, the connection between myosin VI and the transcriptional machinery deserves further analysis, especially in light of suppression of a tumor suppressor gene by myosin VI. In summary, the observation by Dunn et al1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar that myosin VI is overexpressed in prostate cancer will stimulate more molecular studies to understand the function of myosin VI in prostate carcinogenesis. One reason to embark in the analysis of global gene expression differences between normal and cancerous prostate epithelial cells is to determine mechanisms that are responsible for prostate cancer development. In this issue of The American Journal of Pathology, Dunn et al1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar identify myosin VI as a gene that is consistently overexpressed in prostate cancer compared with normal epithelium. Previous studies of myosin VI have revealed overexpression in ovarian cancer and a role of myosin VI in cell migration, endocytosis, and cell polarity.2Cheng KW Lahad JP Kuo WL Lapuk A Yamada K Auersperg N Liu J Smith-McCune K Lu KH Fishman D Gray JW Mills GB The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers.Nat Med. 2004; 10: 1251-1256Crossref PubMed Scopus (413) Google Scholar, 3Buss F Luzio JP Kendrick-Jones J Myosin VI, an actin motor for membrane traffic and cell migration.Traffic. 2002; 3: 851-858Crossref PubMed Scopus (69) Google Scholar, 4Hasson T Myosin VI: two distinct roles in endocytosis.J Cell Sci. 2003; 116: 3453-3461Crossref PubMed Scopus (141) Google Scholar In addition to these cellular processes, which can all be linked to oncogenesis, the study by Dunn et al1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar identifies a novel function of myosin VI. They demonstrate that a sharp decrease in myosin VI expression causes global gene expression changes and reduces the ability of prostate cancer cells to grow as colonies in soft agar. Based on this new insight about the role of myosin VI in prostate cancer, we examine here the broader function of myosin VI during prostate cancer development and cancer cell invasion. Myosin VI Is an Early Marker of Prostate Cancer DevelopmentThe first clue that myosin VI may indeed be an early target of oncogenic transformation in prostate cancer development is the observation that myosin VI is overexpressed in proliferative inflammatory atrophy (PIA)5De Marzo AM Marchi VL Epstein JI Nelson WG Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis.Am J Pathol. 1999; 155: 1985-1992Abstract Full Text Full Text PDF PubMed Scopus (721) Google Scholar and in prostatic intraepithelial neoplasia (PIN).1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar PIN possesses the histopathological features of cancer and is generally recognized as a precursor for invasive carcinoma, but the molecular requirements for progression of PIN to invasive cancer have been difficult to determine. Because myosin VI is uniformly expressed in individual PIN lesions, it is not sufficient for invasion. However, myosin VI expression in PIN strongly suggests that it takes an active role or is at least linked to the selection process of PIN cells that become invasive. Anecdotal evidence supports the concept that invasive cells proliferate slowly,6Klezovitch O Chevillet J Mirosevich J Roberts RL Matusik RJ Vasioukhin V Hepsin promotes prostate cancer progression and metastasis.Cancer Cell. 2004; 6: 185-195Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar and a recent molecular study identifies pathways that are responsible for the reciprocal switches from cell migration and invasion to cell proliferation that may be operational in the progression of PIN to invasive cancer.7Gao CF Xie Q Su YL Koeman J Khoo SK Gustafson M Knudsen BS Hay R Shinomiya N Vande Woude GF Proliferation and invasion: plasticity in tumor cells.Proc Natl Acad Sci USA. 2005; 102: 10528-10533Crossref PubMed Scopus (138) Google Scholar Because myosin VI overexpression increases cell migration, myosin VI most likely facilitates the invasion of PIN cells into the stroma.As demonstrated by Dunn et al,1Dunn TA, Chen S, Faith DA, Hicks JL, Platz EA, Chen Y, Ewing CM, Sauvageot J, Isaacs WB, De Marzo AM, Luo J: A novel role of myosin VI in human prostate cancer. Am J Pathol 169:1843–1854Google Scholar myosin VI is already expressed in the precursor lesion of PIN or PIA. This histological entity is not considered malignant but may be a precursor of malignancy because it is commonly associated with PIN and invasive cancer.8Putzi MJ De Marzo AM Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia.Urology. 2000; 56: 828-832Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Several cancerous molecular changes are detectable in PIA, including hypermethylation of glutathione S-transferase-pi, gain of chromosome 8, and expression of the cell cycle-dependent kinase inhibitor p16.9De Marzo AM DeWeese TL Platz EA Meeker AK Nakayama M Epstein JI Isaacs WB Nelson WG Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment.J Cell Biochem. 2004; 91: 459-477Crossref PubMed Scopus (159) Google Scholar In addition, there is high expression of proteins associated with a stress response, such as cyclooxygenase-210Zha S Gage WR Sauvageot J Saria EA Putzi MJ Ewing CM Faith DA Nelson WG De Marzo AM Isaacs WB Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma.Cancer Res. 2001; 61: 8617-8623PubMed Google Scholar and glutathione-S-transferase A1.11Parsons JK Nelson CP Gage WR Nelson WG Kensler TW De Marzo AM GSTA1 expression in normal, preneoplastic, and neoplastic human prostate tissue.Prostate. 2001; 49: 30-37Crossref PubMed Scopus (82) Google Scholar The expression of myosin VI protein in PIA may be associated with a stress response as well, in particular cell stress in response to DNA damage. In this context, the transcriptional activation of the myosin VI gene may occur through a p53-dependent mechanism on activation of p53 in response to DNA damage.12Jung EJ Liu G Zhou W Chen X Myosin VI is a mediator of the p53-dependent cell survival pathway.Mol Cell Biol. 2006; 26: 2175-2186Crossref PubMed Scopus (59) Google Scholar Because the functional integrity of p53 is probably preserved in PIN cells and only lost later in cancer progression, p53 can induce myosin VI gene transcription in PIN. Thus, myosin VI overexpression occurs before cells become overtly malignant. It appears that overexpression of myosin VI is tolerated during cancer development as cells acquire additional genetic changes. It is likely that some genetic alterations in cancer cells will interact with myosin VI and that the function of myosin VI changes during the development of PIN and the progression to invasive cancer. The first clue that myosin VI may indeed be an early target of oncogenic transformation in prostate cancer development is the observation that myosin VI is overexpressed in proliferative inflammatory atrophy (PIA)5De Marzo AM Marchi VL Epstein JI Nelson WG Proliferative inflammatory atrophy of the prostate: implications
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