Betticher, Daniel C.

RERO DOC Digital Library

Annals of Oncology!: 223-225, 1996.EditorialCyclin Dl, another molecule of the year?One of the aims of carcinogenesis research is to identifythe precise molecular alterations responsible for neo-plastic transformation. Normal cell cycle control is dis-rupted in malignant cells which are unable to regulatetheir proliferation correctly. Understanding how thecell cycle control operates therefore represents a fun-damental problem in cancer biology. Work in recentyears has led to the conclusion that cyclins, and cyctin-dependent kinases (CDKs) together with their inhibi-tors constitute a complicated network of positive andnegative regulation circuits. These basic regulatorymechanisms are common to all mammalian cells andact at specific time points during the cell cycle (FigureDuring the Gl phase, D-type cyclins appear to act asgrowth factor sensors, driving cells through the firstrestriction point (START in yeast), beyond which cellsare committed to divide. Cyclin Dl together with spe-cific kinases (CDK4, CDK6) and one particular kinaseinhibitor (pl6) appears to play a central role in theregulation of the proliferation status. Activated CDK4,through phosphorylation and complex formation withcyclin Dl, inactivates the retinoblastoma protein (pRb).This results in the release from pRb of a transcriptionfactor, E2F, which then activates many genes necessaryfor cell division. The pl6 protein suppresses thisprocess by competitively binding to the CDK4 mol-ecule (Figure 2). Component genes of this specific con-trol pathway are frequently compromised in malignantcells (for review see [1-5]).The apparently ever-growing list of cell cycle regula-tors makes it increasingly difficult to keep abreast ofthis rapidly developing field, let alone for oncologists tothink of clinical applications of these basic discoveries.However, some aspects are becoming clearer withrespect to cancer, one of the most important proteins iscyclin Dl. It is now well established that cyclin Dl hasoncogenic functions: constitutive overexpression inrodent cells can shorten the Gl phase [6], and similarly,in breast cancer cells arrested in Gl, cyclin Dl induc-tion is sufficient to complete the cell cycle and toshorten the Gl-S phase [7]. Transfection of the cyclinDl gene constructs into normal fibroblasts stimulatesproliferation by reduction of the Gl-S phase [6], andwhen transfected into normal fibroblasts with activatedH-ras, it promotes the formation of fibrosarcomas innude mice [8]. Moreover, mice carrying an active cyclinDl transgene develop mammary hyperplasia andadenocarcinoma [9]. When overexpression of cyclin Dlis targeted to the lymphoid system, the transgenic micedevelop lymphomas in the presence of c-myc over-cyclin E+CDK2commitment point(START)cyclin D +CDK4+CDK6cyclin A +CDK2cyclin A and B+ CDK1 (cdc2)Figure I. Combinatorial interactions of cyclins and cyclin depend-ent kinases (CDK) during the cell cycle.Transcription /Induction of the cell cycleCyclin DldegradedG1 TCommitment pointSTARTFigure 2. Model for Gl restriction-point control by cyclin Dl:Growth factors induce the transcription of the cyclin Dl gene(CCND1) and positively regulate its assembly with CDK4 (andCDK6, not shown). The cyclin D1-CDK4 complex is activated bycyclin-activating kinase (CAK - cyclin H + CDK7) and the func-tional holoenzyme then phosphorylates the retinoblastoma protein,releasing and thus activating the E2F transcription factor. TheCDKN2 gene (encoding pl6) inactivates CDK4 and induces accel-erated turnover of unbound cyclin Dl during the S phase.expression [10, 11]. Very recently, cyclin Dl over-expression has been found at early stages of tumourdevelopment, in particular, in carcinoma in situ of thebreast [12] and in bronchial epithelia of resection mar-gins of non-small-cell lung cancer that were micro-scopically tumour-free [13].The region of chromosome I lq l3 encoding thecyclin Dl gene (CCND1) is frequently altered at thecytogenetic level in malignant disease. Increased genecopy numbers (gene amplification) have been found inbreast, ovarian, bladder, esophageal, gallbladder, stom-ach, laryngeal, lung and liver cancers [1]. In esophageal[14], laryngeal [15] and head and neck tumours [16],CCND1 amplification correlates with poor prognosis, ahigh incidence of distant metastasis and frequent recur-rences. In almost all cases, amplification of the I lq l3region was associated with overexpression of cyclin Dl.In lymphoproliferative disorders, another mechanism224may also lead to cyclin Dl overexpression: Transloca-tion between the bcl-1 region, upstream of CCND1,and the immunoglobulin (Ig) heavy chain locus onchromosome 14 [17, 18] results in elevated transcrip-tion of CCND1, with high levels of cyclin Dl [19-22].The translocation t(ll;14Xql3;q32) occurs in 90% ofmantle cell lymphomas and splenic lymphomas withvillous lymphocytes as well as in a small percentage ofcertain aggressive lymphocytic and plasma cell leukae-mias [19-21,23-25].This issue of Annals of Oncology carries an interest-ing paper expanding our knowledge of cyclin Dl inhairy cell leukaemia (HCL). De Boer et al. [26] reporton cyclin Dl overexpression in the majority of patientswith HCL using both molecular and genetic methods.These findings are in full agreement with the veryrecently published study by Bosch et al. [27]. Thirty-eight of 40 HCL patients in the two studies showedcyclin Dl overexpression. The level of expression issignificantly lower than in mantle cell lymphomas;nevertheless, this finding is very interesting and ratherunexpected, given the lack of evidence for molecularlesions involving CCND1 in HCL.Except for some lymphoproliferative disorders withthe bcl-1 rearrangement, lymphoid tissues such as ton-sils, spleen and lymph nodes apparently have no orvery low levels of cyclin Dl expression [19, 28]. DeBoer et al. [26] and Bosch et al. [27] were unable toexplain the mechanism of cyclin Dl overexpressionand CCND1 deregulation in HCL. Neither structuralanomalies within I lq l3 (cytogenetic and moleculartechniques) nor gene amplification were detected. Al-though rearrangements cannot be excluded outside theregions examined, translocation appears not to be amain mechanism responsible for cyclin Dl overexpres-sion in HCL. Although the B-cell lineage of HCL iswell established [29], there are several lines of evidenceindicating some phenotypic and functional similaritiesbetween hairy cells and cells of monocyte/macrophagelineage [30], which normally express cyclin Dl [31].Thus, it remains to be seen whether this cyclin Dl over-expression is at least partially responsible for the malig-nant behaviour of the hairy cells, or whether, as specu-lated by the authors, it might constitute a physiologicalcharacteristic shared by hairy cells. Additionally, it mayrepresent an unspecific upregulation occurring as aresult of the deregulated cycle network. Further work istherefore needed to establish the role of cyclin Dl inHCL.For instance, the examination of allele specificCCND1 expression in HCL would point to a possiblerole in malignancy. Were allelic imbalance observed inPCR-amplified cDNA it might be concluded that onlyone parental allele was responsible for cyclin Dl over-expression. This would lead to the assumption thatthere had been an alteration, such as a mutation withina CCND1 control region or splice site (RNA proces-sing). This phenomenon was recently demonstrated[32, 33]: Using immunostaining in a series of non-small-cell lung tumours, cyclin Dl was overexpressedin almost 30% of cases with no apparent structural ab-normalities of CCND1, as assessed by Southern blot-ting and PCR. In these tumours we detected imbal-ances in allele-specific expression by RT-PCR andrestriction fragment length polymorphism analysis of aHaeIR polymorphism. Thus, genetic alteration ofCCND1 appears to be a key abnormality in lung car-cinogenesis. Such a result in HCL would strengthen theevidence of a direct role for cyclin Dl in the disease.Deregulation or loss of function of genes involved inthe control of progression through the Gl restrictionpoint (CCND1, CDK4, CDKN2, RBI) is common inhuman cancers. Conversely, lesions within the manyother genes controlling aspects of the cell cycle (cyclinA, B, E, CDKs or CDK inhibitor genes) is much lessfrequent. In particular, overexpression of cyclin Dl hasnow been observed in around 50% of the most com-mon and least treatable malignancies, including colo-rectal, head and neck, esophageal, breast, uterus andlung carcinomas, melanomas and sarcomas [14,16, 32,34-37]. In addition, various studies have demonstratedthat blocking the action of cyclin Dl in vitro, with anti-bodies or antisense RNA prevents the growth of manytumour cell lines [6,38]. However, evidence from micein which both parental cyclin Dl genes have beenknocked out suggests that complete loss of cyclin Dlfunction might have only limited effects on overallviability or normal cell proliferation in the adult [39].These findings raise the exciting possibility that thera-peutic agents directed against elements of this pathway,in particular cyclin Dl, might prove not only successfulin the treatment of common malignancies but also haverelatively few side effects. Further research is needed toshow whether such an approach might be transferredfrom the laboratory bench to patients. Should this turnout to be successful, then, without doubt, another edi-torial entitled 'Cyclin Dl, the molecule of the century1will have to be written!Supported by Krebsforschung, Schweiz, KFS 177-9-1995.Daniel C. Betticher, M JJ>.Institute of Medical OncologyInselspital and University of BernBern, SwitzerlandReferences1. Motokura T, Arnold A. Cyclins and oncogenesis. Biochim Bio-phys Acta 1993; 1155:63-78.2. Hunter T, Pines J. Cyclins and cancer II: Cyclin D and CDKinhibitors come of age. Cell 1994; 79: 573-82.3. Sherr CJ. D-type cyclins. Trends Biochem Sri 1995; 20:187-90.4. Sherr CJ, Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev 1995; 9:1149-63.5. Hirama T, Koeffler HP. Role of the cyclin-dependent Itinaseinhibitors in the development of cancer. Blood 1995; 86: 841-54.2256. Quelle DE, Ashmun RA, Shurtleff SA et al. Overexpression ofmouse D-type cyclins accelerates Gl phase in rodent fibro-blasts. Genes Dev 1993; 7:1559-71.7. Musgrove EA, Lee CSL, Buckley MF et al. Cyclin Dl induc-tion in breast cancer cells shorten Gl and is sufficient for cellsarrested in Gl to complete the cell cycle. Proc Natl Acad SciUSA 1994; 91:8022-6.8. Lovec H, Sewing A, Lucibello FC et al. Oncogenic activity ofcyclin Dl revealed through cooperation with Ha-ras: Link be-tween cell cycle control and malignant transformation. Onco-gene 1994; 9: 323-6.9. Wang TC, Cardiff RD, Zukerberg L et al. Mammary hyper-plasia and carcinoma in MMTV-cyclin Dl transgenic mice.Nature 1994; 369: 669-71.10. Bodrug SE, Warner BJ, Bath ML et al. Cyclin Dl transgeneimpedes lymphocyte maturation and collaborates in lympho-magenesis with the myc gene. EMBO J 1994; 13: 2124-30.11. Lovec H, Grzeschiczek A, Kowalski MB et al. Cyclin Cl/bcl-1cooporates with myc genes in the generation of B-cell lym-phoma in transgenic mice. EMBO J 1994; 13: 3487-95.12. Weinstat-Saslow D, Merino MJ, Manrow RE et al. Overexpres-sion of cyclin D mRNA distinguishes invasive and in situ breastcarcinomas from non-malignant lesions. Nature Med 1995; 1:1257-60.13. Betticher DC, Heighway J, Thatcher N et al. Altered CCND1(cyclin Dl) and Rb (retinoblastoma) genes expression is anearly event in non-small cell lung cancer development. Cancerand the Cell Cycle, January 17-20, 1996, Lausanne, Switzer-land, A14.14. Naitoh H, Shibata J, Kawaguchi A et al. Overexpression andlocalization of cyclin Dl mRNA and antigen in esophagealcancer. Am JPathol 1995; 146:1161-9.15. Jares P, Fernandez PL, Campo E et al. PRAD-1/cyclin Dlgene amplification correlates with messenger RNA overexpres-sion and tumor progression in human laryngeal carcinomas.Cancer Res 1994; 54:4813-7.16. Michalides R, Van Veelen N, Hart A et al. Overexpression ofcyclin Dl correlates with recurrence in a group of forty-sevenoperable squamous cell carcinomas of the head and neck. Can-cer Res 1995; 55: 975-8.17. van den Berghe H, Parloir C, David G et al. A new charac-teristic karyotypic anomaly in lymphoproliferative disorders.Cancer 1979; 44:188-95.18. de Boer CJ, Loyson S, Kluin PM et al. Multiple breakpointswithin the bcl-1 locus in B-cell lymphoma: Rearrangements ofthe cyclin Dl gene. Cancer Res 1993; 53:4148-52.19. de Boer CJ, Schuuring E, Dreef E et al. Cyclin Dl proteinanalysis in the diagnosis of mantle cell lymphoma. Blood 1995;86:2715-23.20. Bosch F, Jares P, Campo E et al. PRAD-1/cyclin Dl gene over-expression in chronic lymphoproliferative disorders: A highlyspecific marker of mantle cell lymphoma. Blood 1994; 84:2726-32.21. de Boer CJ, Van Krieken JHJM, Kluin-Neleman HC et al.Cyclin Dl messenger RNA overexpression as a marker formantle cell lymphoma. Oncogene 1995; 10:1833-40.22. Williams ME, Nichols GE, Swerdlow SH. In situ hybridizationdetection of cyclin Dl mRNA in centrocytic/mantle cell lym-phoma. Ann Oncol 1995; 6: 297-9.23. Williams ME, Swerdlow SH. Cyclin Dl overexpression in non-Hodgkin's lymphoma with chromosome 11 bcl-1 rearrange-ment Ann Oncol 1994; 5 (Suppl 1): S71-S73.24. Jadayel D, Matutes E, Dyer MJS et al. Splenic lymphoma withvillous lymphocytes: Analysis of BCL-1 rearrangements andexpression of the cyclin Dl gene. Blood 1994; 83: 3664-71.25. Zukerberg LR, Yang WI, Arnold A et al. Cyclin Dl expressionin non-Hodgkin's lymphomas. Am J Clin Pathol 1995; 103:756-60.26. de Boer CJ, Kluin-Nelemans JC, Dreef E et al. Involvement ofthe CCND1 gene in hairy cell leukemia. Ann Oncol 1996;7: 251-6 (this issue).27. Bosch F, Campo E, Jares P et al. Increased expression of thePRAD-1/CCND1 gene in hairy cell leukaemia. Br J Haematol1995; 91:1025-30.28. Bartkova J, Lukas J, Strauss M et al. Cell cycle-related varia-tion and tissue-restricted expression of human cyclin Dl pro-tein. J Pathol 1994; 172: 237-45.29. Korsmeyer SJ, Greene WC, Cossman J et al. Rearrangementand expression of immunoglobulin genes and expression of theTac antigen in hairy cell leukemia. Proc Natl Acad Sci USA1983; 80:4522-6.30. Golomb HM, Vardiman JW. Hairy-cell leukemia. In WilliamsWJ, Beutler E, Erslev AJ, Lichtman MA (eds): Hematology.Fourth edition, New York: McGraw-Hill Publishing Company1990; 1025-30.31. Matsushime H, Roussel MF, Ashmun RA et al. Colony-stimu-lating factor 1 regulates novel cyclins during the Gl phase ofthe cell cycle. Cell 1991; 65: 701-13.32. Betticher DC, Heighway J, Hasleton PS et al. Prognostic sig-nificance of CCND1 (cyclin Dl) overexpression in primayresected non-small cell lung cancer. Br J Cancer 1996; 73:294-300.33. Betticher DC, Thatcher N, Altermatt HJ et al. Alternate splic-ing produces a novel cyclin Dl transcript. Oncogene 1995; 11:1005-11.34. Bartkova J, Lukas J, Strauss M et al. Cyclin Dl oncoproteinaberrantly accumulates in malignancies of diverse histogenesis.Oncogene 1995; 10: 775-8.35. Bartkova J, Lukas J, Strauss M et al. The PRAD-1/Cyclin Dloncogene product accumulates aberrantly in a subset of colo-rectal carcinomas. Int J Cancer 1994; 58: 568-73.36. Bartkova J, Lukas J, Miiller H et al. Cyclin Dl protein expres-sion and function in human breast cancer. Int J Cancer 1994;57:353-61.37. Gillett C, Fantl V, Smith R et al. Amplification and overexpres-sion of cyclin Dl in breast cancer detected by immunohisto-chemical staining. Cancer Res 1994; 54:1812-7.38. Zhou P, Jiang W, Zhang YJ et al. Antisense to cyclin Dlinhibits growth and reverses the transformed phenotype ofhuman esophageal cancer cells. Oncogene 1995; 11: 571-80.39. Sicinski P, Donaher JL, Parker SB et al. Cyclin Dl provides alink between development and oncogenesis in the retina andbreast Cell 1995; 82:621-30.

Cyclin D1, another molecule of the year?

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library