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. 2017 Oct 23;8(61):103428-103436.
doi: 10.18632/oncotarget.21952. eCollection 2017 Nov 28.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Aly-Khan A Lalani  1 , Kathryn P Gray  2 , Laurence Albiges  3 , Marcella Callea  4 , Jean-Christophe Pignon  5 , Soumitro Pal  6 , Mamta Gupta  7 , Rupal S Bhatt  8 , David F McDermott  8 , Michael B Atkins  9 , G F Vande Woude  10 , Lauren C Harshman  1 , Toni K Choueiri  1 , Sabina Signoretti  5
Affiliations

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression

Aly-Khan A Lalani et al. Oncotarget. .

Abstract

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Keywords: PD-L1; c-Met; metastasis; primary; renal cell carcinoma.

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Conflict of interest statement

CONFLICTS OF INTEREST AAL: educational travel support from Pfizer. KPG: stock and other ownership interests in MDGN. LA: research funding from Novartis and Pfizer; advisory role at Novartis, Pfizer, Amgen and Sanofi. DFM: consulting/advisory role at Alexion Pharmaceuticals, Array BioPharma, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, X4 Pharma; institutional research funding from Prometheus Labs. MBA: honoraria from Bristol-Myers Squibb; consulting/advisory role at Alkermes, Amgen, Bristol-Myers Squibb, C-Cam, Genentech, Genoptix, GlaxoSmithKline, Infinity Pharmaceuticals, Lilly, Merck, Nektar, Novartis, Pfizer, X4 Pharma. LCH: consulting/advisory role at Dendreon, Genentech, KEW Group, Medivation/Astellas, NCCN, Pfizer, PlatformQ Health, Theragene; institutional research funding from Bayer, Dendreon, Genentech/Roche, Medivation/Astellas, Sotio, Takeda, Bristol-Myers Squibb; Travel, Accommodations, and Expenses from Sanofi. TKC: honoraria from NCCN, UpToDate; consulting/advisory role at Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Pfizer; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Exelixis, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech, TRACON Pharma. SS: consulting/advisory role at AstraZeneca, Merck, Verastem; institutional research funding from AstraZeneca and Exelixis; patents or other intellectual property at Biogenex. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative images of a primary ccRCC (A) and its corresponding metastasis (B) immunostained for c-Met. A, weak (1+) membranous staining is observed in a subset of tumor cells. B, intense (3+) membranous staining is observed in a large fraction of tumor cells. Insets show higher magnifications of the selected areas. Scale bars: 50 µm.
Figure 2
Figure 2. Distributions of c-Met expression according to PD-L1 staining positivity (PD-L1+, > 0% positive cells vs. PD-L1-, = 0% positive cells) based on tumor sample sites
Figure 3
Figure 3
Representative images of two ccRCC metastases immunostained for PD-L1 (A, C) and c-Met (Met; B, D). PD-L1 positive metastasis (A) with intense (3+) membranous c-Met staining (B). PD-L1 negative metastasis (C) with weak (1+) membranous c-Met staining (D). Scale bars: 50 µm.
See this image and copyright information in PMC

References

    1. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251:802–804. - PubMed
    1. Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res. 2006;12:3657–3660. - PubMed
    1. Harshman LC, Choueiri TK. Targeting the Hepatocyte Growth Factor/c-Met Signaling Pathway in Renal Cell Carcinoma. Cancer J. 2013;19:316–323. - PubMed
    1. Guo B, Cen H, Tan X, Liu W, Ke Q. Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures. PLoS One. 2014;9:e99399. - PMC - PubMed
    1. Gao H, Guan M, Sun Z, Bai C. High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis. Tumour Biol. 2015;36:515–520. - PubMed