Skip to main content
Top
Published in: Tumor Biology 3/2014

01-03-2014 | Research Article

Overexpression of stathmin 1 confers an independent prognostic indicator in nasopharyngeal carcinoma

Authors: Han-Ping Hsu, Chien-Feng Li, Sung-Wei Lee, Wen-Ren Wu, Tzu-Ju Chen, Kwang-Yu Chang, Shih-Shin Liang, Chia-Jung Tsai, Yow-Ling Shiue

Published in: Tumor Biology | Issue 3/2014

Login to get access

Abstract

Data mining on public domain identified that stathmin 1 (STMN1) transcript was significantly higher expressed in nasopharyngeal carcinoma (NPC). Also known as the oncoprotein 18, STMN1 performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cellular conditions. Immunoexpression of STMN1 was retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The outcome was correlated with clinicopathological features and patient survivals. Results indicated that high STMN1 expressions (50 %) were correlated with advanced age (p = 0.027), higher T stage (p = 0.003), and overall clinical stage (p = 0.006) by the 7th American Joint Committee of Cancer Staging. In multivariate analyses, high STMN1 expression emerged as an independent prognosticator for worse disease-specific survival (p = 0.001), distal metastasis-free survival (p = 0.003), and local recurrence-free survival (p = 0.006). Exogenous expression of E2F transcription factor 1 (E2F1) or/and its dimeric partner, transcription factor Dp-1 (TFDP1), notably induced the STMN1 protein level in a NPC-derived cell line, TW01. Accordingly, high STMN1 protein level is commonly associated with adverse prognosticators and confers tumor aggressiveness in patients with NPC, and its upregulation might be attributed to E2F1 and/or TFDP1 transactivation.
Literature
2.
go back to reference Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15:1765–77.PubMedCrossRef Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15:1765–77.PubMedCrossRef
3.
go back to reference Jeyakumar A, Brickman TM, Doerr T: Review of nasopharyngeal carcinoma. Ear Nose Throat J 2006;85:168–170, 172–163, 184. Jeyakumar A, Brickman TM, Doerr T: Review of nasopharyngeal carcinoma. Ear Nose Throat J 2006;85:168–170, 172–163, 184.
4.
go back to reference Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27:242–9.PubMedCrossRef Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27:242–9.PubMedCrossRef
5.
go back to reference Boekelheide K, Arcila ME, Eveleth J. Cis-diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics. Toxicol Appl Pharmacol. 1992;116:146–51.PubMedCrossRef Boekelheide K, Arcila ME, Eveleth J. Cis-diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics. Toxicol Appl Pharmacol. 1992;116:146–51.PubMedCrossRef
6.
go back to reference Peyrot V, Briand C, Momburg R, Sari JC. In vitro mechanism study of microtubule assembly inhibition by cis-dichlorodiammine-platinum(II). Biochemical pharmacology. 1986;35:371–5.PubMedCrossRef Peyrot V, Briand C, Momburg R, Sari JC. In vitro mechanism study of microtubule assembly inhibition by cis-dichlorodiammine-platinum(II). Biochemical pharmacology. 1986;35:371–5.PubMedCrossRef
7.
go back to reference Tulub AA, Stefanov VE. Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes. International journal of biological macromolecules. 2001;28:191–8.PubMedCrossRef Tulub AA, Stefanov VE. Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes. International journal of biological macromolecules. 2001;28:191–8.PubMedCrossRef
8.
go back to reference Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer. 2010;10:194–204.PubMedCrossRef Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer. 2010;10:194–204.PubMedCrossRef
9.
go back to reference Lee SW, Chen TJ, Lin LC, Li CF, Chen LT, Hsing CH, et al. Overexpression of thymidylate synthetase confers an independent prognostic indicator in nasopharyngeal carcinoma. Exp Mol Pathol. 2013;95:83–90.PubMedCrossRef Lee SW, Chen TJ, Lin LC, Li CF, Chen LT, Hsing CH, et al. Overexpression of thymidylate synthetase confers an independent prognostic indicator in nasopharyngeal carcinoma. Exp Mol Pathol. 2013;95:83–90.PubMedCrossRef
10.
go back to reference Cassimeris L. The oncoprotein 18/stathmin family of microtubule destabilizers. Current opinion in cell biology. 2002;14:18–24.PubMedCrossRef Cassimeris L. The oncoprotein 18/stathmin family of microtubule destabilizers. Current opinion in cell biology. 2002;14:18–24.PubMedCrossRef
11.
go back to reference Ringhoff DN, Cassimeris L. Stathmin regulates centrosomal nucleation of microtubules and tubulin dimer/polymer partitioning. Mol Biol Cell. 2009;20:3451–8.PubMedCentralPubMedCrossRef Ringhoff DN, Cassimeris L. Stathmin regulates centrosomal nucleation of microtubules and tubulin dimer/polymer partitioning. Mol Biol Cell. 2009;20:3451–8.PubMedCentralPubMedCrossRef
12.
go back to reference Sobel A. Stathmin: a relay phosphoprotein for multiple signal transduction? Trends Biochem Sci. 1991;16:301–5.PubMedCrossRef Sobel A. Stathmin: a relay phosphoprotein for multiple signal transduction? Trends Biochem Sci. 1991;16:301–5.PubMedCrossRef
13.
go back to reference Alli E, Bash-Babula J, Yang JM, Hait WN. Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res. 2002;62:6864–9.PubMed Alli E, Bash-Babula J, Yang JM, Hait WN. Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res. 2002;62:6864–9.PubMed
14.
go back to reference Wolden SL, Zelefsky MJ, Kraus DH, Rosenzweig KE, Chong LM, Shaha AR, et al. Accelerated concomitant boost radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma. J Clin Oncol. 2001;19:1105–10.PubMed Wolden SL, Zelefsky MJ, Kraus DH, Rosenzweig KE, Chong LM, Shaha AR, et al. Accelerated concomitant boost radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma. J Clin Oncol. 2001;19:1105–10.PubMed
15.
go back to reference Chen YL, Uen YH, Li CF, Horng KC, Chen LR, Wu WR, et al. The E2F transcription factor 1 transactives stathmin 1 in hepatocellular carcinoma. Ann Surg Oncol. 2013;20(12):4041–54.PubMedCrossRef Chen YL, Uen YH, Li CF, Horng KC, Chen LR, Wu WR, et al. The E2F transcription factor 1 transactives stathmin 1 in hepatocellular carcinoma. Ann Surg Oncol. 2013;20(12):4041–54.PubMedCrossRef
16.
go back to reference Cheng AL, Huang WG, Chen ZC, Peng F, Zhang PF, Li MY, et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res. 2008;14:435–45.PubMedCrossRef Cheng AL, Huang WG, Chen ZC, Peng F, Zhang PF, Li MY, et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res. 2008;14:435–45.PubMedCrossRef
17.
go back to reference Iancu-Rubin C, Nasrallah CA, Atweh GF: Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation. Cell cycle (Georgetown, Tex) 2005;4:1774–1782. Iancu-Rubin C, Nasrallah CA, Atweh GF: Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation. Cell cycle (Georgetown, Tex) 2005;4:1774–1782.
18.
go back to reference Kouzu Y, Uzawa K, Koike H, Saito K, Nakashima D, Higo M, et al. Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis. Br J Cancer. 2006;94:717–23.PubMedCentralPubMed Kouzu Y, Uzawa K, Koike H, Saito K, Nakashima D, Higo M, et al. Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis. Br J Cancer. 2006;94:717–23.PubMedCentralPubMed
19.
go back to reference Melhem RF, Zhu XX, Hailat N, Strahler JR, Hanash SM. Characterization of the gene for a proliferation-related phosphoprotein (oncoprotein 18) expressed in high amounts in acute leukemia. J Biol Chem. 1991;266:17747–53.PubMed Melhem RF, Zhu XX, Hailat N, Strahler JR, Hanash SM. Characterization of the gene for a proliferation-related phosphoprotein (oncoprotein 18) expressed in high amounts in acute leukemia. J Biol Chem. 1991;266:17747–53.PubMed
20.
go back to reference Ghosh PK, Anderson J, Cohen N, Takeshita K, Atweh GF, Lebowitz P. Expression of the leukemia-associated gene, p18, in normal and malignant tissues; inactivation of expression in a patient with cleaved b cell lymphoma/leukemia. Oncogene. 1993;8:2869–72.PubMed Ghosh PK, Anderson J, Cohen N, Takeshita K, Atweh GF, Lebowitz P. Expression of the leukemia-associated gene, p18, in normal and malignant tissues; inactivation of expression in a patient with cleaved b cell lymphoma/leukemia. Oncogene. 1993;8:2869–72.PubMed
21.
go back to reference Brattsand G. Correlation of oncoprotein 18/stathmin expression in human breast cancer with established prognostic factors. Br J Cancer. 2000;83:311–8.PubMedCentralPubMedCrossRef Brattsand G. Correlation of oncoprotein 18/stathmin expression in human breast cancer with established prognostic factors. Br J Cancer. 2000;83:311–8.PubMedCentralPubMedCrossRef
22.
go back to reference Chen G, Wang H, Gharib TG, Huang CC, Thomas DG, Shedden KA, et al. Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas. Mol Cell Proteomics. 2003;2:107–16.PubMedCrossRef Chen G, Wang H, Gharib TG, Huang CC, Thomas DG, Shedden KA, et al. Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas. Mol Cell Proteomics. 2003;2:107–16.PubMedCrossRef
23.
go back to reference Jeon TY, Han ME, Lee YW, Lee YS, Kim GH, Song GA, et al. Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells. Br J Cancer. 2010;102:710–8.PubMedCentralPubMedCrossRef Jeon TY, Han ME, Lee YW, Lee YS, Kim GH, Song GA, et al. Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells. Br J Cancer. 2010;102:710–8.PubMedCentralPubMedCrossRef
24.
go back to reference Hsieh SY, Huang SF, Yu MC, Yeh TS, Chen TC, Lin YJ, et al. Stathmin1 overexpression associated with polyploidy, tumor-cell invasion, early recurrence, and poor prognosis in human hepatoma. Mol Carcinog. 2010;49:476–87.PubMed Hsieh SY, Huang SF, Yu MC, Yeh TS, Chen TC, Lin YJ, et al. Stathmin1 overexpression associated with polyploidy, tumor-cell invasion, early recurrence, and poor prognosis in human hepatoma. Mol Carcinog. 2010;49:476–87.PubMed
25.
go back to reference Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, et al. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol. 2006;209:549–58.PubMedCrossRef Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, et al. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol. 2006;209:549–58.PubMedCrossRef
26.
go back to reference Su D, Smith SM, Preti M, Schwartz P, Rutherford TJ, Menato G, et al. Stathmin and tubulin expression and survival of ovarian cancer patients receiving platinum treatment with and without paclitaxel. Cancer. 2009;115:2453–63.PubMedCrossRef Su D, Smith SM, Preti M, Schwartz P, Rutherford TJ, Menato G, et al. Stathmin and tubulin expression and survival of ovarian cancer patients receiving platinum treatment with and without paclitaxel. Cancer. 2009;115:2453–63.PubMedCrossRef
27.
go back to reference Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of pi3 kinase activation. Proc Natl Acad Sci U S A. 2009;106:4834–9.PubMedCentralPubMedCrossRef Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of pi3 kinase activation. Proc Natl Acad Sci U S A. 2009;106:4834–9.PubMedCentralPubMedCrossRef
28.
go back to reference Xi W, Rui W, Fang L, Ke D, Ping G, Hui-Zhong Z. Expression of stathmin/op18 as a significant prognostic factor for cervical carcinoma patients. J Cancer Res Clin Oncol. 2009;135:837–46.PubMedCrossRef Xi W, Rui W, Fang L, Ke D, Ping G, Hui-Zhong Z. Expression of stathmin/op18 as a significant prognostic factor for cervical carcinoma patients. J Cancer Res Clin Oncol. 2009;135:837–46.PubMedCrossRef
29.
go back to reference Mistry SJ, Atweh GF. Therapeutic interactions between stathmin inhibition and chemotherapeutic agents in prostate cancer. Mol Cancer Ther. 2006;5:3248–57.PubMedCrossRef Mistry SJ, Atweh GF. Therapeutic interactions between stathmin inhibition and chemotherapeutic agents in prostate cancer. Mol Cancer Ther. 2006;5:3248–57.PubMedCrossRef
30.
go back to reference Zheng P, Liu YX, Chen L, Liu XH, Xiao ZQ, Zhao L, et al. Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer. J Proteome Res. 2010;9:4897–905.PubMedCrossRef Zheng P, Liu YX, Chen L, Liu XH, Xiao ZQ, Zhao L, et al. Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer. J Proteome Res. 2010;9:4897–905.PubMedCrossRef
31.
go back to reference Karst AM, Levanon K, Duraisamy S, Liu JF, Hirsch MS, Hecht JL, et al. Stathmin 1, a marker of pi3k pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. Gynecol Oncol. 2011;2011:17. Karst AM, Levanon K, Duraisamy S, Liu JF, Hirsch MS, Hecht JL, et al. Stathmin 1, a marker of pi3k pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. Gynecol Oncol. 2011;2011:17.
32.
go back to reference Prota AE, Bargsten K, Zurwerra D, Field JJ, Diaz JF, Altmann KH, et al. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science. 2013;339:587–90.PubMedCrossRef Prota AE, Bargsten K, Zurwerra D, Field JJ, Diaz JF, Altmann KH, et al. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science. 2013;339:587–90.PubMedCrossRef
33.
go back to reference Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiother Oncol. 2011;98:15–22.PubMedCrossRef Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, et al. A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiother Oncol. 2011;98:15–22.PubMedCrossRef
34.
go back to reference Jeha S, Luo XN, Beran M, Kantarjian H, Atweh GF. Antisense rna inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer Res. 1996;56:1445–50.PubMed Jeha S, Luo XN, Beran M, Kantarjian H, Atweh GF. Antisense rna inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer Res. 1996;56:1445–50.PubMed
35.
go back to reference Misek DE, Chang CL, Kuick R, Hinderer R, Giordano TJ, Beer DG, et al. Transforming properties of a q18 e mutation of the microtubule regulator op18. Cancer Cell. 2002;2:217–28.PubMedCrossRef Misek DE, Chang CL, Kuick R, Hinderer R, Giordano TJ, Beer DG, et al. Transforming properties of a q18 e mutation of the microtubule regulator op18. Cancer Cell. 2002;2:217–28.PubMedCrossRef
36.
go back to reference Belletti B, Nicoloso MS, Schiappacassi M, Berton S, Lovat F, Wolf K, et al. Stathmin activity influences sarcoma cell shape, motility, and metastatic potential. Mol Biol Cell. 2008;19:2003–13.PubMedCentralPubMedCrossRef Belletti B, Nicoloso MS, Schiappacassi M, Berton S, Lovat F, Wolf K, et al. Stathmin activity influences sarcoma cell shape, motility, and metastatic potential. Mol Biol Cell. 2008;19:2003–13.PubMedCentralPubMedCrossRef
37.
go back to reference Gan L, Guo K, Li Y, Kang X, Sun L, Shu H, et al. Up-regulated expression of stathmin may be associated with hepatocarcinogenesis. Oncol Rep. 2010;23:1037–43.PubMed Gan L, Guo K, Li Y, Kang X, Sun L, Shu H, et al. Up-regulated expression of stathmin may be associated with hepatocarcinogenesis. Oncol Rep. 2010;23:1037–43.PubMed
39.
go back to reference Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene. 2005;24:2810–26.PubMedCrossRef Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene. 2005;24:2810–26.PubMedCrossRef
40.
go back to reference Helin K. Regulation of cell proliferation by the E2F transcription factors. Current Opinion in Genetics & Development. 1998;8:28–35.CrossRef Helin K. Regulation of cell proliferation by the E2F transcription factors. Current Opinion in Genetics & Development. 1998;8:28–35.CrossRef
41.
go back to reference Takahashi Y, Rayman JB, Dynlacht BD. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 2000;14:804–16.PubMedCentralPubMed Takahashi Y, Rayman JB, Dynlacht BD. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 2000;14:804–16.PubMedCentralPubMed
42.
go back to reference Li J, Ran C, Li E, Gordon F, Comstock G, Siddiqui H, et al. Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev Cell. 2008;14:62–75.PubMedCentralPubMedCrossRef Li J, Ran C, Li E, Gordon F, Comstock G, Siddiqui H, et al. Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev Cell. 2008;14:62–75.PubMedCentralPubMedCrossRef
43.
go back to reference Helin K, Wu CL, Fattaey AR, Lees JA, Dynlacht BD, Ngwu C, et al. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 1993;7:1850–61.PubMedCrossRef Helin K, Wu CL, Fattaey AR, Lees JA, Dynlacht BD, Ngwu C, et al. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 1993;7:1850–61.PubMedCrossRef
44.
go back to reference DeGregori J, Kowalik T, Nevins JR. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and g1/s-regulatory genes. Mol Cell Biol. 1995;15:4215–24.PubMedCentralPubMed DeGregori J, Kowalik T, Nevins JR. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and g1/s-regulatory genes. Mol Cell Biol. 1995;15:4215–24.PubMedCentralPubMed
45.
46.
go back to reference Bracken AP, Ciro M, Cocito A, Helin K. E2f target genes: Unraveling the biology. Trends Biochem Sci. 2004;29:409–17.PubMedCrossRef Bracken AP, Ciro M, Cocito A, Helin K. E2f target genes: Unraveling the biology. Trends Biochem Sci. 2004;29:409–17.PubMedCrossRef
47.
go back to reference Le QT, Tate D, Koong A, Gibbs IC, Chang SD, Adler JR, et al. Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2003;56:1046–54.PubMedCrossRef Le QT, Tate D, Koong A, Gibbs IC, Chang SD, Adler JR, et al. Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2003;56:1046–54.PubMedCrossRef
Metadata
Title
Overexpression of stathmin 1 confers an independent prognostic indicator in nasopharyngeal carcinoma
Authors
Han-Ping Hsu
Chien-Feng Li
Sung-Wei Lee
Wen-Ren Wu
Tzu-Ju Chen
Kwang-Yu Chang
Shih-Shin Liang
Chia-Jung Tsai
Yow-Ling Shiue
Publication date
01-03-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 3/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-1345-3

Other articles of this Issue 3/2014

Tumor Biology 3/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine