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Published in: Endocrine Pathology 2/2019

01-06-2019 | Thyroid Cancer

Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis

Authors: Chiara Saglietti, Stefano La Rosa, Gerasimos P. Sykiotis, Igor Letovanec, Jean-Luc Bulliard, Simonetta Piana, Maxime Mermod, Tatiana Petrova, Silvia Uccella, Fausto Sessa, Massimo Bongiovanni

Published in: Endocrine Pathology | Issue 2/2019

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Abstract

Medullary thyroid carcinoma (MTC) has been shown to express Prospero homeobox protein 1 (Prox1), a transcription factor whose expression is altered in a variety of human cancers. We conducted a retrospective study on a series of 32 patients with MTC to test the correlation of Prox1 expression in MTC with clinicopathological features and to evaluate its prognostic significance. Correlation of Prox1 immunohistochemical expression with tumor size, proliferative index (Ki67), and calcitonin and CEA serum levels prior to surgery was tested for significant correlations. The difference in Prox1 and Ki67 immunohistochemical expression according to the immunohistochemical staining intensity of CEA, chromogranin A, and calcitonin was tested using the Kruskal-Wallis H test and linear regression analysis. The prognostic value of Prox1 and Ki67 for our patient cohort was assessed by Kaplan-Meier log rank survival analysis. We demonstrated a positive correlation between Prox1 expression and Ki67 index. Prox1 also showed significant difference in expression according to chromogranin A and calcitonin immunohistochemical expression, with higher Prox1 expression in tumors with stronger chromogranin A or calcitonin staining. Prox1 expression did not correlate with PFS or OS based on Kaplan-Meier log rank survival analysis. In conclusion, Prox1 expression in MTC is positively correlated with Ki67 and with the immunohistochemical expression of chromogranin A and calcitonin. However, the present study does not support a role for Prox1 in MTC prognosis.
Literature
1.
go back to reference Wells SA, Jr., Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25:567–610CrossRefPubMedPubMedCentral Wells SA, Jr., Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25:567–610CrossRefPubMedPubMedCentral
2.
go back to reference Raue F, Frank-Raue K (2015) Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma. Recent Results Cancer Res 204:61–90CrossRefPubMed Raue F, Frank-Raue K (2015) Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma. Recent Results Cancer Res 204:61–90CrossRefPubMed
3.
go back to reference Jaskula-Sztul R, Eide J, Tesfazghi S, Dammalapati A, Harrison AD, Yu XM, Scheinebeck C, Winston-McPherson G, Kupcho KR, Robers MB, Hundal AK, Tang W, Chen H (2015) Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction. Mol Cancer Ther 14:499–512CrossRefPubMed Jaskula-Sztul R, Eide J, Tesfazghi S, Dammalapati A, Harrison AD, Yu XM, Scheinebeck C, Winston-McPherson G, Kupcho KR, Robers MB, Hundal AK, Tang W, Chen H (2015) Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction. Mol Cancer Ther 14:499–512CrossRefPubMed
4.
go back to reference Hundahl SA, Fleming ID, Fremgen AM, Menck HR (1998) A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 15:2638–2648CrossRef Hundahl SA, Fleming ID, Fremgen AM, Menck HR (1998) A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 15:2638–2648CrossRef
5.
go back to reference Piana S, Frasoldati A, Di Felice E, Gardini G, Tallini G, Rosai J (2010) Encapsulated well-differentiated follicular-patterned thyroid carcinomas do not play a significant role in the fatality rates from thyroid carcinoma. Am J Surg Pathol 34:868–872CrossRefPubMed Piana S, Frasoldati A, Di Felice E, Gardini G, Tallini G, Rosai J (2010) Encapsulated well-differentiated follicular-patterned thyroid carcinomas do not play a significant role in the fatality rates from thyroid carcinoma. Am J Surg Pathol 34:868–872CrossRefPubMed
6.
go back to reference Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P, Leclerc L, Corcuff B, Guilhem I (1998) Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC study group. Groupe d’étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 48:265–273CrossRef Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, Schlumberger M, Bigorgne JC, Dumontier P, Leclerc L, Corcuff B, Guilhem I (1998) Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC study group. Groupe d’étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 48:265–273CrossRef
7.
go back to reference DeLellis RA, Al Ghuzlan A, Albores Saavedra J, Baloch ZW, Basolo F, Eliseri R, et al (2017) Medullary thyroid carcinoma. In: Lloyd R, Osamura RY, Kloppel G, Rosai J (ed) WHO Classification of Tumours of Endocrine Organs, 4th edn. IARC, Lyon, pp 211–214 DeLellis RA, Al Ghuzlan A, Albores Saavedra J, Baloch ZW, Basolo F, Eliseri R, et al (2017) Medullary thyroid carcinoma. In: Lloyd R, Osamura RY, Kloppel G, Rosai J (ed) WHO Classification of Tumours of Endocrine Organs, 4th edn. IARC, Lyon, pp 211–214
8.
go back to reference Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH (2000) Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88:1139–1148.CrossRef Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH (2000) Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88:1139–1148.CrossRef
9.
go back to reference Scopsi L, Sampietro G, Boracchi P, Del Bo R, Gullo M, Placucci M, Pilotti S (1996) Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer 78:2173–2183CrossRefPubMed Scopsi L, Sampietro G, Boracchi P, Del Bo R, Gullo M, Placucci M, Pilotti S (1996) Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer 78:2173–2183CrossRefPubMed
10.
go back to reference Tisell LE, Oden A, Muth A, Altipamark G, Molne J, Ahlman H, Nilsson O (2003) The Ki67 index as a prognostic marker in medullary thyroid carcinoma. Br J Cancer 89:2093–2097CrossRefPubMedPubMedCentral Tisell LE, Oden A, Muth A, Altipamark G, Molne J, Ahlman H, Nilsson O (2003) The Ki67 index as a prognostic marker in medullary thyroid carcinoma. Br J Cancer 89:2093–2097CrossRefPubMedPubMedCentral
11.
go back to reference DeLellis RA, Mangray, S (2017) Medullary thyroid carcinoma: a contemporary perspective. AJSP-Reviews and Reports 22:196–208 DeLellis RA, Mangray, S (2017) Medullary thyroid carcinoma: a contemporary perspective. AJSP-Reviews and Reports 22:196–208
12.
go back to reference Choi D, Ramu S, Park E, Jung E, Yang S, Jung W, Choi I, Lee S, Kim KE, Seong YJ, Hong M, Daghlian G, Kim D, Shin E, Seo JI, Khatchadourian V, Zou M, Li W, de Filippo R, Kokorowski P, Chang A, Kim S, Bertoni A, Furlanetto TW, Shin S, Li M, Chen Y, Wong A, Koh C, Geliebter J, Hong YK (2016) Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells. Cancer Res 76:582–593CrossRefPubMed Choi D, Ramu S, Park E, Jung E, Yang S, Jung W, Choi I, Lee S, Kim KE, Seong YJ, Hong M, Daghlian G, Kim D, Shin E, Seo JI, Khatchadourian V, Zou M, Li W, de Filippo R, Kokorowski P, Chang A, Kim S, Bertoni A, Furlanetto TW, Shin S, Li M, Chen Y, Wong A, Koh C, Geliebter J, Hong YK (2016) Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells. Cancer Res 76:582–593CrossRefPubMed
13.
go back to reference Ishii J, Yazawa T, Chiba T, Shishido-Hara Y, Arimasu Y, Sato H, Kamma H (2016) PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells. Endocrinology 157:1289–1298CrossRefPubMed Ishii J, Yazawa T, Chiba T, Shishido-Hara Y, Arimasu Y, Sato H, Kamma H (2016) PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells. Endocrinology 157:1289–1298CrossRefPubMed
14.
go back to reference Elsir T, Smits A, Lindstrom MS, Nistér M (2012) Transcription factor PROX1: its role in development and cancer. Cancer metastasis reviews 31:793–805CrossRefPubMed Elsir T, Smits A, Lindstrom MS, Nistér M (2012) Transcription factor PROX1: its role in development and cancer. Cancer metastasis reviews 31:793–805CrossRefPubMed
15.
go back to reference Lavado A, Oliver G (2007) Prox1 expression patterns in the developing and adult murine brain. Dev Dyn 236:518–524CrossRefPubMed Lavado A, Oliver G (2007) Prox1 expression patterns in the developing and adult murine brain. Dev Dyn 236:518–524CrossRefPubMed
16.
go back to reference Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357CrossRefPubMed Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357CrossRefPubMed
17.
go back to reference Wigle JT, Chowdhury K, Gruss P, Oliver G (1999) Prox1 function is crucial for mouse lens-fibre elongation. Nature Genet 21:318–322CrossRefPubMed Wigle JT, Chowdhury K, Gruss P, Oliver G (1999) Prox1 function is crucial for mouse lens-fibre elongation. Nature Genet 21:318–322CrossRefPubMed
18.
go back to reference Burke Z, Oliver G. Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118:147–155, 2002CrossRefPubMed Burke Z, Oliver G. Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118:147–155, 2002CrossRefPubMed
19.
go back to reference Dyer MA, Livesey FJ, Cepko CL, Oliver G (2003) Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 34:53–58CrossRefPubMed Dyer MA, Livesey FJ, Cepko CL, Oliver G (2003) Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 34:53–58CrossRefPubMed
20.
go back to reference Risebro CA, Searles RG, Melville AA, Ehler E, Jina N, Shah S, et al (2009) Prox1 maintains muscle structure and growth in the developing heart. Development 136:495–505CrossRefPubMed Risebro CA, Searles RG, Melville AA, Ehler E, Jina N, Shah S, et al (2009) Prox1 maintains muscle structure and growth in the developing heart. Development 136:495–505CrossRefPubMed
21.
go back to reference Petrova TV, Mäkinen T, Mäkelä TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593–4599CrossRefPubMedPubMedCentral Petrova TV, Mäkinen T, Mäkelä TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21:4593–4599CrossRefPubMedPubMedCentral
22.
go back to reference Jernman J, Kallio P, Hagstrom J, Valimaki MJ, Haapasalo H, Alitalo K, Arola J, Haglund C (2015) PROX1 is involved in progression of rectal neuroendocrine tumors, NETs. Virch Archiv 467:279–284CrossRef Jernman J, Kallio P, Hagstrom J, Valimaki MJ, Haapasalo H, Alitalo K, Arola J, Haglund C (2015) PROX1 is involved in progression of rectal neuroendocrine tumors, NETs. Virch Archiv 467:279–284CrossRef
23.
go back to reference American Joint Committee on Cancer. Thyroid – Medullary. In: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017: 891. American Joint Committee on Cancer. Thyroid – Medullary. In: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017: 891.
24.
go back to reference Pan DH, Wen DY, Luo YH, Chen G, Yang H, Chen JQ, He Y (2017) The diagnostic and prognostic values of Ki-67/MIB-1 expression in thyroid cancer: a meta-analysis with 6,051 cases. Onco Targets Ther 10:3261–3276CrossRefPubMedPubMedCentral Pan DH, Wen DY, Luo YH, Chen G, Yang H, Chen JQ, He Y (2017) The diagnostic and prognostic values of Ki-67/MIB-1 expression in thyroid cancer: a meta-analysis with 6,051 cases. Onco Targets Ther 10:3261–3276CrossRefPubMedPubMedCentral
26.
go back to reference Hadoux J, Schlumberger M (2017) Chemotherapy and tyrosine-kinase inhibitors for medullary thyroid cancer. Best Pract Res Clin Endocrinol Metab 31:335–347CrossRefPubMed Hadoux J, Schlumberger M (2017) Chemotherapy and tyrosine-kinase inhibitors for medullary thyroid cancer. Best Pract Res Clin Endocrinol Metab 31:335–347CrossRefPubMed
27.
go back to reference Liu JW, Chen C, Loh EW, Chu CC, Wang MY, Ouyang HJ, Chang YT, Zhuang WZ, Chou CW, Huang DJ, Lee CH, Yen Y, Tam KW (2018) Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials. Curr Med Res Opinion 34:795–803CrossRef Liu JW, Chen C, Loh EW, Chu CC, Wang MY, Ouyang HJ, Chang YT, Zhuang WZ, Chou CW, Huang DJ, Lee CH, Yen Y, Tam KW (2018) Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials. Curr Med Res Opinion 34:795–803CrossRef
28.
go back to reference Elsir T, Eriksson A, Orrego A, Lindstrom MS, Nistér M (2010) Expression of PROX1 Is a common feature of high-grade malignant astrocytic gliomas. J Neuropathol Exp Neurol 69:129–138CrossRefPubMed Elsir T, Eriksson A, Orrego A, Lindstrom MS, Nistér M (2010) Expression of PROX1 Is a common feature of high-grade malignant astrocytic gliomas. J Neuropathol Exp Neurol 69:129–138CrossRefPubMed
29.
go back to reference Liu Y, Ye X, Zhang JB, Ouyang H, Shen Z, Wu Y, Wang W, Wu J, Tao S, Yang X, Qiao K, Zhang J, Liu J, Fu Q, Xie Y (2015) PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing beta-catenin expression and nuclear translocation. Oncogene 34:5524–5535CrossRefPubMed Liu Y, Ye X, Zhang JB, Ouyang H, Shen Z, Wu Y, Wang W, Wu J, Tao S, Yang X, Qiao K, Zhang J, Liu J, Fu Q, Xie Y (2015) PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing beta-catenin expression and nuclear translocation. Oncogene 34:5524–5535CrossRefPubMed
30.
go back to reference Dudas J, Mansuroglu T, Moriconi F, Haller F, Wilting J, Lorf T, Fuzesi L, Ramadori G (2008) Altered regulation of Prox1-gene-expression in liver tumors. BMC Cancer 8:92CrossRefPubMedPubMedCentral Dudas J, Mansuroglu T, Moriconi F, Haller F, Wilting J, Lorf T, Fuzesi L, Ramadori G (2008) Altered regulation of Prox1-gene-expression in liver tumors. BMC Cancer 8:92CrossRefPubMedPubMedCentral
31.
go back to reference Shimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H (2006) A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res 12:6005–6011CrossRefPubMed Shimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H (2006) A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res 12:6005–6011CrossRefPubMed
32.
go back to reference Wiener Z, Hogstrom J, Hyvonen V, Band AM, Kallio P, Holopainen T, et al (2014) Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep 8:1943–1956CrossRefPubMed Wiener Z, Hogstrom J, Hyvonen V, Band AM, Kallio P, Holopainen T, et al (2014) Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep 8:1943–1956CrossRefPubMed
33.
go back to reference Skog M, Bono P, Lundin M, Louhimo J, Linder N, Petrova TV, Andersson LC, Joensuu H, Alitalo K, Haglund CH (2011) Expression and prognostic value of transcription factor PROX1 in colorectal cancer. Br J Cancer 105:1346–1351CrossRefPubMedPubMedCentral Skog M, Bono P, Lundin M, Louhimo J, Linder N, Petrova TV, Andersson LC, Joensuu H, Alitalo K, Haglund CH (2011) Expression and prognostic value of transcription factor PROX1 in colorectal cancer. Br J Cancer 105:1346–1351CrossRefPubMedPubMedCentral
34.
go back to reference Petrova TV, Nykanen A, Norrmen C, Ivanov KI, Andersson LC, Haglund C, et al (2008) Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13:407–419CrossRefPubMed Petrova TV, Nykanen A, Norrmen C, Ivanov KI, Andersson LC, Haglund C, et al (2008) Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13:407–419CrossRefPubMed
35.
go back to reference Ragusa S, Cheng J, Ivanov KI, Zannger N, Ceteci F, Bernier-Latmani J, et al (2014) PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt (high) metastatic colon cancer cells. Cell Rep 8:1957–1973CrossRefPubMed Ragusa S, Cheng J, Ivanov KI, Zannger N, Ceteci F, Bernier-Latmani J, et al (2014) PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt (high) metastatic colon cancer cells. Cell Rep 8:1957–1973CrossRefPubMed
36.
go back to reference Gramolelli S, Cheng J, Martinez-Corral I, Vaha-Koskela M, Elbasani E, Kaivanto E, et al (2018) PROX1 is a transcriptional regulator of MMP14. Sci Rep 8:9531CrossRefPubMedPubMedCentral Gramolelli S, Cheng J, Martinez-Corral I, Vaha-Koskela M, Elbasani E, Kaivanto E, et al (2018) PROX1 is a transcriptional regulator of MMP14. Sci Rep 8:9531CrossRefPubMedPubMedCentral
Metadata
Title
Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis
Authors
Chiara Saglietti
Stefano La Rosa
Gerasimos P. Sykiotis
Igor Letovanec
Jean-Luc Bulliard
Simonetta Piana
Maxime Mermod
Tatiana Petrova
Silvia Uccella
Fausto Sessa
Massimo Bongiovanni
Publication date
01-06-2019
Publisher
Springer US
Published in
Endocrine Pathology / Issue 2/2019
Print ISSN: 1046-3976
Electronic ISSN: 1559-0097
DOI
https://doi.org/10.1007/s12022-019-9576-5

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