Skip to main content
Erschienen in: Medical Oncology 7/2018

01.07.2018 | Original Paper

Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma

verfasst von: Yuji Konishi, Futoshi Kawamata, Hiroshi Nishihara, Shigenori Homma, Yasutaka Kato, Masumi Tsuda, Shinji Kohsaka, Takahiro Einama, Cheng Liu, Tadashi Yoshida, Akihisa Nagatsu, Mishie Tanino, Shinya Tanaka, Hideki Kawamura, Toshiya Kamiyama, Akinobu Taketomi

Erschienen in: Medical Oncology | Ausgabe 7/2018

Einloggen, um Zugang zu erhalten

Abstract

Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an “EMT phenotype” who may respond to targeted molecular therapies.
Literatur
1.
Zurück zum Zitat Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed
2.
Zurück zum Zitat Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R. Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol. 2012;25(10):1315–25.CrossRefPubMed Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R. Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol. 2012;25(10):1315–25.CrossRefPubMed
4.
Zurück zum Zitat Ueno H, Price AB, Wilkinson KH, Jass JR, Mochizuki H, Talbot IC. A new prognostic staging system for rectal cancer. Ann Surg. 2004;240(5):832–9.CrossRefPubMedPubMedCentral Ueno H, Price AB, Wilkinson KH, Jass JR, Mochizuki H, Talbot IC. A new prognostic staging system for rectal cancer. Ann Surg. 2004;240(5):832–9.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Okuyama T, Oya M, Ishikawa H. Budding as a risk factor for lymph node metastasis in pT1 or pT2 well-differentiated colorectal adenocarcinoma. Dis Colon Rectum. 2002;45(5):628 – 34.CrossRefPubMed Okuyama T, Oya M, Ishikawa H. Budding as a risk factor for lymph node metastasis in pT1 or pT2 well-differentiated colorectal adenocarcinoma. Dis Colon Rectum. 2002;45(5):628 – 34.CrossRefPubMed
6.
Zurück zum Zitat Hase K, Shatney C, Johnson D, Trollope M, Vierra M. Prognostic value of tumor “budding” in patients with colorectal cancer. Dis Colon Rectum. 1993;36(7):627 – 35.CrossRefPubMed Hase K, Shatney C, Johnson D, Trollope M, Vierra M. Prognostic value of tumor “budding” in patients with colorectal cancer. Dis Colon Rectum. 1993;36(7):627 – 35.CrossRefPubMed
7.
Zurück zum Zitat Ueno H, Mochizuki H, Shinto E, Hashiguchi Y, Hase K, Talbot IC. Histologic indices in biopsy specimens for estimating the probability of extended local spread in patients with rectal carcinoma. Cancer. 2002;94(11):2882–91.CrossRefPubMed Ueno H, Mochizuki H, Shinto E, Hashiguchi Y, Hase K, Talbot IC. Histologic indices in biopsy specimens for estimating the probability of extended local spread in patients with rectal carcinoma. Cancer. 2002;94(11):2882–91.CrossRefPubMed
8.
Zurück zum Zitat Bradley CA, Dunne PD, Bingham V, McQuaid S, Khawaja H, Craig S, et al. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer. Oncotarget. 2016;7(48):78932–45.CrossRefPubMedPubMedCentral Bradley CA, Dunne PD, Bingham V, McQuaid S, Khawaja H, Craig S, et al. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer. Oncotarget. 2016;7(48):78932–45.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488 – 94.CrossRefPubMed Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488 – 94.CrossRefPubMed
11.
Zurück zum Zitat Galvan JA, Helbling M, Koelzer VH, Tschan MP, Berger MD, Hadrich M, et al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget. 2015;6(2):874 – 85.CrossRefPubMed Galvan JA, Helbling M, Koelzer VH, Tschan MP, Berger MD, Hadrich M, et al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget. 2015;6(2):874 – 85.CrossRefPubMed
12.
Zurück zum Zitat Zlobec I, Lugli A. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget. 2010;1(7):651–61.PubMedPubMedCentral Zlobec I, Lugli A. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget. 2010;1(7):651–61.PubMedPubMedCentral
14.
Zurück zum Zitat Lundin M, Nordling S, Lundin J, Alfthan H, Stenman UH, Haglund C. Tissue expression of human chorionic gonadotropin beta predicts outcome in colorectal cancer: a comparison with serum expression. Int J Cancer. 2001;95(1):18–22.CrossRefPubMed Lundin M, Nordling S, Lundin J, Alfthan H, Stenman UH, Haglund C. Tissue expression of human chorionic gonadotropin beta predicts outcome in colorectal cancer: a comparison with serum expression. Int J Cancer. 2001;95(1):18–22.CrossRefPubMed
15.
Zurück zum Zitat Louhimo J, Kokkola A, Alfthan H, Stenman UH, Haglund C. Preoperative hCGbeta and CA 72-4 are prognostic factors in gastric cancer. Int J Cancer. 2004;111(6):929–33.CrossRefPubMed Louhimo J, Kokkola A, Alfthan H, Stenman UH, Haglund C. Preoperative hCGbeta and CA 72-4 are prognostic factors in gastric cancer. Int J Cancer. 2004;111(6):929–33.CrossRefPubMed
16.
Zurück zum Zitat Louhimo J, Alfthan H, Stenman UH, Haglund C. Serum HCG beta and CA 72-4 are stronger prognostic factors than CEA, CA 19-9 and CA 242 in pancreatic cancer. Oncology. 2004;66(2):126–31.CrossRefPubMed Louhimo J, Alfthan H, Stenman UH, Haglund C. Serum HCG beta and CA 72-4 are stronger prognostic factors than CEA, CA 19-9 and CA 242 in pancreatic cancer. Oncology. 2004;66(2):126–31.CrossRefPubMed
17.
Zurück zum Zitat Butler SA, Ikram MS, Mathieu S, Iles RK. The increase in bladder carcinoma cell population induced by the free beta subunit of human chorionic gonadotrophin is a result of an anti-apoptosis effect and not cell proliferation. Br J Cancer. 2000;82(9):1553–6.CrossRefPubMedPubMedCentral Butler SA, Ikram MS, Mathieu S, Iles RK. The increase in bladder carcinoma cell population induced by the free beta subunit of human chorionic gonadotrophin is a result of an anti-apoptosis effect and not cell proliferation. Br J Cancer. 2000;82(9):1553–6.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, et al. Crystal structure of human chorionic gonadotropin. Nature. 1994;369(6480):455–61.CrossRefPubMed Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, et al. Crystal structure of human chorionic gonadotropin. Nature. 1994;369(6480):455–61.CrossRefPubMed
19.
Zurück zum Zitat Kawamata F, Nishihara H, Homma S, Kato Y, Tsuda M, Konishi Y, et al. Chorionic Gonadotropin-beta Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis. Am J Pathol. 2018;188(1):204–15.CrossRefPubMed Kawamata F, Nishihara H, Homma S, Kato Y, Tsuda M, Konishi Y, et al. Chorionic Gonadotropin-beta Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis. Am J Pathol. 2018;188(1):204–15.CrossRefPubMed
20.
Zurück zum Zitat Sobin LH, Compton CC. TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 2010;116(22):5336–9.CrossRefPubMed Sobin LH, Compton CC. TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 2010;116(22):5336–9.CrossRefPubMed
21.
Zurück zum Zitat Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40(2):127–32.CrossRefPubMed Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40(2):127–32.CrossRefPubMed
22.
Zurück zum Zitat Oh BY, Park YA, Huh JW, Yun SH, Kim HC, Chun HK, et al. Prognostic impact of tumor-budding grade in stages 1–3 colon cancer: a retrospective cohort study. Ann Surg Oncol. 2018;25(1):204 – 11.CrossRefPubMed Oh BY, Park YA, Huh JW, Yun SH, Kim HC, Chun HK, et al. Prognostic impact of tumor-budding grade in stages 1–3 colon cancer: a retrospective cohort study. Ann Surg Oncol. 2018;25(1):204 – 11.CrossRefPubMed
23.
Zurück zum Zitat Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713–29.CrossRefPubMed Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713–29.CrossRefPubMed
24.
Zurück zum Zitat Kuramochi H, Nakamura A, Nakajima G, Kaneko Y, Araida T, Yamamoto M, et al. PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study. BMC Cancer. 2016;16:366.CrossRefPubMedPubMedCentral Kuramochi H, Nakamura A, Nakajima G, Kaneko Y, Araida T, Yamamoto M, et al. PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study. BMC Cancer. 2016;16:366.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30(9):1299–311.CrossRef Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30(9):1299–311.CrossRef
26.
Zurück zum Zitat Horst D, Budczies J, Brabletz T, Kirchner T, Hlubek F. Invasion associated up-regulation of nuclear factor kappaB target genes in colorectal cancer. Cancer. 2009;115(21):4946–58.CrossRefPubMed Horst D, Budczies J, Brabletz T, Kirchner T, Hlubek F. Invasion associated up-regulation of nuclear factor kappaB target genes in colorectal cancer. Cancer. 2009;115(21):4946–58.CrossRefPubMed
27.
Zurück zum Zitat Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T. Heterogeneous expression of Wnt/beta-catenin target genes within colorectal cancer. Int J Cancer. 2007;121(9):1941–8.CrossRefPubMed Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T. Heterogeneous expression of Wnt/beta-catenin target genes within colorectal cancer. Int J Cancer. 2007;121(9):1941–8.CrossRefPubMed
28.
Zurück zum Zitat De Smedt L, Palmans S, Andel D, Govaere O, Boeckx B, Smeets D, et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer. 2017;116(1):58–65.CrossRefPubMed De Smedt L, Palmans S, Andel D, Govaere O, Boeckx B, Smeets D, et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer. 2017;116(1):58–65.CrossRefPubMed
29.
Zurück zum Zitat Zlobec I, Molinari F, Martin V, Mazzucchelli L, Saletti P, Trezzi R, et al. Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients. World J Gastroenterol. 2010;16(38):4823–31.CrossRefPubMedPubMedCentral Zlobec I, Molinari F, Martin V, Mazzucchelli L, Saletti P, Trezzi R, et al. Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients. World J Gastroenterol. 2010;16(38):4823–31.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Moulton HM, Yoshihara PH, Mason DH, Iversen PL, Triozzi PL. Active specific immunotherapy with a beta-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival. Clin Cancer Res. 2002;8(7):2044–51.PubMed Moulton HM, Yoshihara PH, Mason DH, Iversen PL, Triozzi PL. Active specific immunotherapy with a beta-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival. Clin Cancer Res. 2002;8(7):2044–51.PubMed
31.
Zurück zum Zitat Berndt S, Blacher S, Munaut C, Detilleux J, Perrier d’Hauterive S, Huhtaniemi I, et al. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation. FASEB J. 2013;27(4):1309–21.CrossRefPubMed Berndt S, Blacher S, Munaut C, Detilleux J, Perrier d’Hauterive S, Huhtaniemi I, et al. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation. FASEB J. 2013;27(4):1309–21.CrossRefPubMed
32.
Zurück zum Zitat Gulubova M, Manolova I, Ananiev J, Julianov A, Yovchev Y, Peeva K. Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer. Int J Colorectal Dis. 2010;25(5):591–9.CrossRefPubMed Gulubova M, Manolova I, Ananiev J, Julianov A, Yovchev Y, Peeva K. Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer. Int J Colorectal Dis. 2010;25(5):591–9.CrossRefPubMed
33.
Zurück zum Zitat Liu XQ, Rajput A, Geng L, Ongchin M, Chaudhuri A, Wang J. Restoration of transforming growth factor-beta receptor II expression in colon cancer cells with microsatellite instability increases metastatic potential in vivo. J Biol Chem. 2011;286(18):16082–90.CrossRefPubMedPubMedCentral Liu XQ, Rajput A, Geng L, Ongchin M, Chaudhuri A, Wang J. Restoration of transforming growth factor-beta receptor II expression in colon cancer cells with microsatellite instability increases metastatic potential in vivo. J Biol Chem. 2011;286(18):16082–90.CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Lehnert SA, Akhurst RJ. Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development. 1988;104(2):263 – 73.PubMed Lehnert SA, Akhurst RJ. Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development. 1988;104(2):263 – 73.PubMed
35.
Zurück zum Zitat Fujii D, Brissenden JE, Derynck R, Francke U. Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat Cell Mol Genet. 1986;12(3):281–8.CrossRefPubMed Fujii D, Brissenden JE, Derynck R, Francke U. Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat Cell Mol Genet. 1986;12(3):281–8.CrossRefPubMed
Metadaten
Titel
Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma
verfasst von
Yuji Konishi
Futoshi Kawamata
Hiroshi Nishihara
Shigenori Homma
Yasutaka Kato
Masumi Tsuda
Shinji Kohsaka
Takahiro Einama
Cheng Liu
Tadashi Yoshida
Akihisa Nagatsu
Mishie Tanino
Shinya Tanaka
Hideki Kawamura
Toshiya Kamiyama
Akinobu Taketomi
Publikationsdatum
01.07.2018
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 7/2018
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-018-1164-x

Weitere Artikel der Ausgabe 7/2018

Medical Oncology 7/2018 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.