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01-02-2005 | Original Article

Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma

Authors: I. D. Nagtegaal, C. G. S. Gaspar, L. T. C. Peltenburg, C. A. M. Marijnen, E. Kapiteijn, C. J. H. van de Velde, R. Fodde, J. H. J. M. van Krieken

Published in: Virchows Archiv | Issue 2/2005

Abstract

Purpose

Radiotherapy is a very effective adjuvant treatment for rectal cancer with little side effects. Its killing effect on tumor cells seems to be more profound than the effect on normal tissue. The molecular events caused by irradiation are mainly analyzed in in vitro and animal models; investigations on human material are rare. In the current study, we analyzed the effects of irradiation on gene expression in normal and tumor tissue of rectal cancer patients.

Methods and materials

Normal and carcinoma tissue of patients from a randomized clinical trial of the benefits of preoperative radiotherapy were analyzed using the Affymetrix Human Cancer Gene Chip. Preoperative radiotherapy was given within 5 days prior to surgery. Results for normal tissue and tumor were compared to investigate the radiation-related differences between normal and tumor cells. We clustered the differentially expressed genes based on their functional annotation. Results were compared with immunohistochemical and literature data.

Results

The majority of the investigated cancer-related genes remained unchanged by irradiation (92% in tumor tissue and 93% in normal tissue). The differentially expressed genes varied between tumor and normal tissue except for maspin and IL-8. Both in tumor and normal tissue, differentially expressed genes were present related to cell signaling and cycle control, apoptosis and cell survival and tissue response and repair. However, the spectrum of affected genes was totally different.

Conclusion

Pre-existing differences in gene expression between normal tissue and tumor tissue might explain the differences in their responses to radiation. This change in response may explain the clinical beneficial effect of radiotherapy on tumor cells (low local recurrence rate) and the less severe effects on normal tissue (minor side effects).

Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L (2001) Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem 276:28261–28267PubMed

Artuso M, Esteve A, Bresil H, Vuillaume M, Hall J (1995) The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. Oncogene 11:1427–1435PubMed

Bus PJ, Nagtegaal ID, Verspaget HW, Lamers CBHW, van Krieken JHJM, Griffioen G (1999) Mesazaline-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era? Aliment Pharmacol Ther 13:1397–1402

Cuenca RE, Azizkhan RG, Haskill S (1992) Characterization of GRO alpha, beta and gamma expression in human colonic tumours: potential significance of cytokine involvement. Surg Oncol 1:323–329PubMed

de Fraipont F, Nicholson AC, Feige JJ, VanMeir EG (2001) Thrombospondins and tumor angiogenesis. Trends Mol Med 7:401–407PubMed

Ebara T, Mitsuhashi N, Saito Y, Akimoto T, Niibe H (1998) Change in E-cadherin expression after X-ray irradiation of a human cancer cell line in vitro and in vivo. Int J Radiat Oncol Biol Phys 41:669–674PubMed

Fornace AJ Jr (1992) Mammalian genes induced by radiation; activation of genes associated with growth control. Annu Rev Genet 26:507–526PubMed

Hockerfelt U, Henriksson R, Franzen L, Norrgard O, Forsgren S (1999) Irradiation induces marked immunohistochemical expression of vasoactive intestinal peptide in colonic mucosa of man. Dig Dis Sci 44:393–401PubMed

Hopeweel JW, Young CMA (1978) Changes in the microcirculation of normal tissues after irradiation. Int J Radiat Oncol Biol Phys 4:53–58PubMed

10.

Jin H, Yang R, Awad TA, Wang F, Li W, Williams SP, Ogasawara A, Shimada B, Williams PM, de Feo G, Paoni NF (2001) Effects of early angiotensin-converting enzyme inhibition on cardiac gene expression after acute myocardial infarction. Circulation 103:736–742PubMed

11.

Kapiteijn E, Marijnen CAM, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJT, Pahlman L, Glimelius B, van Krieken JHJM, Leer JWH, van de Velde CJH (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. New Engl J Med 345:638–646PubMed

12.

Kitahara O, Furukawa Y, Tanaka T, Kihara C, Ono K, Yanagawa R, Nita ME, Takagi T, Nakamura Y, Tsunoda T (2001) Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res 61:3544–3549PubMed

13.

Knebel A, Bohmer FD, Herrlich P (2000) Radiation-induced signal transduction. Methods Enzymol 319:255–272PubMed

14.

Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258:1798–1801PubMed

15.

Krishnan L, Krishnan EC, Jewell WR (1988) Immediate effect of irradiation on microvasculature. Int J Radiat Oncol Biol Phys 15:147–150PubMed

16.

Kumar A, Collins H, van Tam J, Scholefield JH, Watson SA (2002) Effect of preoperative radiotherapy on matrilysin gene expression in rectal cancer. Eur J Cancer 38:505–510PubMed

17.

Langberg CW, Hauer-Jensen M, Sung CC, Kane CJM (1994) Expression of fibrogenic cytokines in rat small intestine after fractionated irradiation. Radiother Oncol 32:29–36PubMed

18.

Li Y, Jenkins CW, Nichols MA, Xiong Y (1994) Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene 9:2261–2268PubMed

19.

Liu M, Dhanwada KR, Birt DF, Hecht S, Pelling JC (1994) Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation. Carcinogenesis 15:1089–1092

20.

Marijnen CAM, Nagtegaal ID, Klein Kranenbarg E, Hermans J, van de Velde CJH, Leer JWH, van Krieken JHJM, Pathology Review Committee (2001) No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 19:1976–1984PubMed

21.

Marijnen CAM, Kapiteijn E, Nagtegaal ID, Mulder A, van de Velde CJH, Schrier PI, Peltenburg LTC, van Krieken JHJM (2002) p53 expression in rectal tissue after radiotherapy: remarkable long-term upregulation in normal mucosa versus extreme high frequency of functional loss in rectal carcinoma. Int J Radiation Oncology Biol Phys 52:720–728

22.

Marijnen CAM, Kapiteijn E, van de Velde CJH, Martijn H, Steup WH, Wiggers T, Klein Kranenbarg E, Leer JWH (2002) Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter trial. J Clin Oncol 20:817–825PubMed

23.

Nagtegaal ID, Klein Kranenbarg E, Hermans J, van de Velde CJH, van Krieken JHJM, Pathology Review Committee (2000) Pathology data in the central database of multicenter randomized trials need to be based on pathology reports and controlled by trained quality managers. J Clin Oncol 18:1771–1779PubMed

24.

Nagtegaal ID, Marijnen CAM, Klein Kranenbarg E, Mulder A, Hermans J, van de Velde CJH, van Krieken JHJM (2001) Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only systemic effect—a histopathological and immunohistochemical study. BMC Cancer 1:7PubMed

25.

Nagtegaal ID, Marijnen CAM, Klein Kranenbarg E, Mulder A, Hermans J, van de Velde CJH, van Krieken JHJM (2002) Short-term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer. J Pathol 197:20–27PubMed

26.

Ng IO, Lam KY, Ng M, Kwong DL, Sham JS (1998) Expression of P-glycoprotein, a multidrug-resistance gene product, is induced by radiotherapy in patients with oral squamous cell carcinoma. Cancer 83:851–857PubMed

27.

Notterman DA, Alon U, Sierk AJ, Levine AJ (2001) Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res 61:3124–3130PubMed

28.

Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Kolesnick R (2001) Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293:293–297PubMed

29.

Renehan AG, Bach SP, Potten CS (2001) The relevance of apoptosis for cellular homeostasis and tumorigenesis in the intestine. Can J Gastroenterol 15:166–176PubMed

30.

Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83:4167–4171PubMed

31.

Rosen EM, Fan S, Rockwell S, Goldberg ID (1999) The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Invest 17:56–72PubMed

32.

Schmidt-Ullrich RK, Dent P, Mikkelsen RB, Valerie K (2000) Signal transduction and cellular radiation responses. Radiat Res 153:245–257PubMed

33.

Seidita G, Polizzi D, Costanzo G, Costa S, Di Leonardo A (2000) Differential gene expression in p53-mediated G(1) arrest of human fibroblasts after gamma-irradiation or N-phosphoacetyl-L-aspartate treatment. Carcinogenesis 21:2203–2210PubMed

34.

Thiagarajah JR, Gourmelon P, Griffiths NM, Lebrun F, Naftalin RJ, Pedley KC (2000) Radiation induced cytochrome c release causes loss of rat colonic fluid absorption by damage to crypts and pericryptal myofibroblasts. Gut 47:675–684PubMed

35.

Thykjaer T, Workman C, Kruhoffer M, Demtroder K, Wolf H, Andersen LD, Frederiksen CM, Knudsen S, Orntoft TF (2001) Identification of gene expression patterns in superficial and invasive human bladder cancer. Cancer Res 61:2492–2499PubMed

36.

Wang H, Chakrabarty S (2001) Requirement of protein kinase Calpha, extracellular matrix remodeling, and cell-matrix interaction for transforming growth factor beta-regulated expression of E-cadherin and catenins. J Cell Physiol 187:188–195PubMed

37.

Xiao G, Chicas A, Olivier M, Taya Y, Tyagi S, Kramer FR, Bargonetti J (2000) A DNA damage signal is required for p53 to activate gadd45. Cancer Res 60:1711–1719PubMed

38.

Yamakawa T, Kurosawa N, Kadomatsu K, Matsui T, Itoh K, Maeda N, Noda M, Muramatsu T (1999) Levels of expression of pleiotrophin and protein tyrosine phosphatase zeta are decreased in human colorectal cancers. Cancer Lett 135:91–96PubMed

39.

Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S (2000) p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem 275:6051–6054PubMed

Title: Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma
Authors: I. D. Nagtegaal
C. G. S. Gaspar
L. T. C. Peltenburg
C. A. M. Marijnen
E. Kapiteijn
C. J. H. van de Velde
R. Fodde
J. H. J. M. van Krieken
Publication date: 01-02-2005
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 2/2005
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-004-1160-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma

Abstract

Purpose

Methods and materials

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods and materials

Results

Conclusion

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