Profiling Immunohistochemical Expression of NOTCH1-3, JAGGED1, CMET, and Phospho-MAPK in 100 Carcinomas of Unknown Primary

Overview

Journal Clin Exp Metastasis

Specialty Oncology

Date 2012 Apr 25

PMID 22526456

Citations 9

Authors

Dimitrios Krikelis

George Pentheroudakis

Anna Goussia

Vassiliki Siozopoulou

Mattheos Bobos

Dimitrios Petrakis

Aikaterini Stoyianni

Vassilios Golfinopoulos

Andres Cervantes

Tudor Ciuleanu

George Fountzilas

Vassiliki Malamou-Mitsi

Nicholas Pavlidis

Affiliations

Soon will be listed here.

Abstract

Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation.

Citing Articles

Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary.

Cavazzoni A, Salamon I, Fumarola C, Gallerani G, Laprovitera N, Gelsomino F Mol Ther. 2024; 32(10):3650-3668.

PMID: 39033323 PMC: 11489551. DOI: 10.1016/j.ymthe.2024.07.011.

The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients.

Ristic Petrovic A, Stokanovic D, Stojnev S, Potic Floranovic M, Krstic M, Djordjevic I Bosn J Basic Med Sci. 2022; 22(4):523-530.

PMID: 35073251 PMC: 9392971. DOI: 10.17305/bjbms.2021.6767.

Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition.

Verginelli F, Pisacane A, Gambardella G, DAmbrosio A, Candiello E, Ferrio M Nat Commun. 2021; 12(1):2498.

PMID: 33941777 PMC: 8093243. DOI: 10.1038/s41467-021-22643-w.

Progress in refining the clinical management of cancer of unknown primary in the molecular era.

Rassy E, Pavlidis N Nat Rev Clin Oncol. 2020; 17(9):541-554.

PMID: 32350398 DOI: 10.1038/s41571-020-0359-1.

Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?.

Rassy E, Assi T, Pavlidis N Br J Cancer. 2020; 122(8):1124-1132.

PMID: 32042068 PMC: 7156745. DOI: 10.1038/s41416-019-0723-z.

References

Pavlidis N, Briassoulis E, Bai M, Fountzilas G, Agnantis N . Overexpression of C-myc, Ras and C-erbB-2 oncoproteins in carcinoma of unknown primary origin. Anticancer Res. 1995; 15(6B):2563-7. View

Kim C, Kim J, Kahng H, Choi E . Change of E-cadherin by hepatocyte growth factor and effects on the prognosis of hypopharyngeal carcinoma. Ann Surg Oncol. 2007; 14(5):1565-74. DOI: 10.1245/s10434-006-9320-5. View

Dova L, Pentheroudakis G, Georgiou I, Malamou-Mitsi V, Vartholomatos G, Fountzilas G . Global profiling of EGFR gene mutation, amplification, regulation and tissue protein expression in unknown primary carcinomas: to target or not to target?. Clin Exp Metastasis. 2007; 24(2):79-86. DOI: 10.1007/s10585-007-9055-0. View

Gu F, Ma Y, Zhang Z, Zhao J, Kobayashi H, Zhang L . Expression of Stat3 and Notch1 is associated with cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 2010; 23(3):671-6. DOI: 10.3892/or_00000683. View

McShane L, Altman D, Sauerbrei W, Taube S, Gion M, Clark G . Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005; 23(36):9067-72. DOI: 10.1200/JCO.2004.01.0454. View

Davis J, Navolanic P, Weinstein-Oppenheimer C, Steelman L, Hu W, Konopleva M . Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance. Clin Cancer Res. 2003; 9(3):1161-70. View

Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Kalofonos H . Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1. BMC Cancer. 2005; 5:25. PMC: 555600. DOI: 10.1186/1471-2407-5-25. View

Dova L, Pentheroudakis G, Golfinopoulos V, Malamou-Mitsi V, Georgiou I, Vartholomatos G . Targeting c-KIT, PDGFR in cancer of unknown primary: a screening study for molecular markers of benefit. J Cancer Res Clin Oncol. 2007; 134(6):697-704. DOI: 10.1007/s00432-007-0341-7. View

Miele L . Notch signaling. Clin Cancer Res. 2006; 12(4):1074-9. DOI: 10.1158/1078-0432.CCR-05-2570. View

10.

Radtke F, Raj K . The role of Notch in tumorigenesis: oncogene or tumour suppressor?. Nat Rev Cancer. 2003; 3(10):756-67. DOI: 10.1038/nrc1186. View

11.

Briasoulis E, Tsokos M, Fountzilas G, Bafaloukos D, Kosmidis P, Samantas E . Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study. Anticancer Res. 1998; 18(3B):1907-14. View

12.

Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V . Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Res. 2010; 70(21):8874-85. DOI: 10.1158/0008-5472.CAN-10-1994. View

13.

Inno A, Di Salvatore M, Cenci T, Martini M, Orlandi A, Strippoli A . Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?. Clin Colorectal Cancer. 2011; 10(4):325-32. DOI: 10.1016/j.clcc.2011.03.028. View

14.

Borggrefe T, Oswald F . The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 2009; 66(10):1631-46. PMC: 11115614. DOI: 10.1007/s00018-009-8668-7. View

15.

Wang Z, Li Y, Banerjee S, Sarkar F . Emerging role of Notch in stem cells and cancer. Cancer Lett. 2008; 279(1):8-12. PMC: 2699045. DOI: 10.1016/j.canlet.2008.09.030. View

16.

Seiwert T, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M . The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009; 69(7):3021-31. PMC: 2871252. DOI: 10.1158/0008-5472.CAN-08-2881. View

17.

McCubrey J, Steelman L, Chappell W, Abrams S, Wong E, Chang F . Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2006; 1773(8):1263-84. PMC: 2696318. DOI: 10.1016/j.bbamcr.2006.10.001. View

18.

Crosswell H, Dasgupta A, Alvarado C, Watt T, Christensen J, De P . PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells. BMC Cancer. 2009; 9:411. PMC: 2790467. DOI: 10.1186/1471-2407-9-411. View

19.

Harrison H, Farnie G, Howell S, Rock R, Stylianou S, Brennan K . Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 2010; 70(2):709-18. PMC: 3442245. DOI: 10.1158/0008-5472.CAN-09-1681. View

20.

Haruki N, Kawaguchi K, Eichenberger S, Massion P, Olson S, Gonzalez A . Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers. Cancer Res. 2005; 65(9):3555-61. DOI: 10.1158/0008-5472.CAN-04-3132. View