Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases

Chaux, Alcides; Munari, Enrico; Cubilla, Antonio L.; Hicks, Jessica L.; Lecksell, Kristen; Burnett, Arthur L.; Netto, George J.

doi:10.1111/his.12338

Cited by 25 publications

(19 citation statements)

References 16 publications

(37 reference statements)

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“…The activation of the mTOR signaling pathway has recently been demonstrated in penile SCC (Chaux et al, 2014;Ferr andiz-Pulido et al, 2013a). Moreover, epidermal growth factor receptor (EGFR) is overexpressed in more than 90% of penile SCC (Lavens et al, 2010;Gou et al, 2013) and retrospective studies suggest that EGFR inhibitors may be active in this context (Carthon et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Identification of somatic gene mutations in penile squamous cell carcinoma

Ferrándiz-Pulido

Hernández‐Losa

Masferrer

et al. 2015

Genes Chromosomes & Cancer

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There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

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Section: Introductionmentioning

confidence: 99%

Identification of somatic gene mutations in penile squamous cell carcinoma

Ferrándiz-Pulido

Hernández‐Losa

Masferrer

et al. 2015

Genes Chromosomes & Cancer

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“…Multiple oncogenic signaling pathways including STAT3, PI3K/AKT, and metaloproteinases MMP2/9 contribute to PC carcinogenesis. Stankiewicz and Chaux et al showed that AKT expression positively correlated with tumor grade and prognosis of PC 39 , 40 . Yang et al identified STAT3 as one of the top oncogenic pathways upregulated in PC 41 .…”

Section: Discussionmentioning

confidence: 99%

High serum CCL20 is associated with tumor progression in penile cancer

Tong

Huang

et al. 2020

J. Cancer

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Serum cancer biomarker has been proven to be very valuable in cancer diagnosis, disease monitoring and prognosis assessment, despite there is still a lack of serum biomarker for penile cancer (PC). Our initial analysis on public GEO dataset identified CCL20 as a top C-C motif ligand (CCL) gene enriched in PC. The patients with PC exhibited markedly higher preoperative serum CCL20 level than healthy control. The area under the curve (AUC) was 0.855 with the sensitivity of 72.4%, and specificity of 93.5% to distinguish PC. Preoperative serum CCL20 level was significantly associated with clinicopathological characteristics including T stage ( P =0.005), nodal status ( P =0.008), and pelvic lymph node metastasis ( P =0.007). PC Patients with high serum CCL20 level had shorter disease-free survival compared to those with low level ( P <0.001). Cox regression analysis showed that serum CCL20 level could serve as an independent prognostic factor for disease-free survival with a HR of 3.980 (95% CI: 1.209-13.098, P =0.023). Furthermore, CCL20 expression was observed in PC tissues and cell lines. Knockdown of CCL20 expression markedly suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration and invasion), attenuated STAT3 and AKT signaling and reduced MMP2/9 secretion in PC cell lines. Consistently, CCL20 and its receptor CCR6 exhibited correlated expression pattern in PC tissues. In conclusion, serum CCL20 level might serve as a potential diagnostic and prognostic cancer biomarker for PC. CCL20 might activate multiple downstream oncogenic signaling pathways (STAT3, AKT, MMP2/9) to promote malignant progression of PC, which may warrant further investigation in the future.

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“…In penile squamous cell carcinoma, mTOR has been shown to be overexpressed in histologically high grade cases ( 27 ). BxPC-3 cells with enriched fibroblasts may have been in a histologically high grade due to mTOR expression at the time of transplantation.…”

Section: Discussionmentioning

confidence: 99%

ASF-4-1 fibroblast-rich culture increases chemoresistance and mTOR expression of pancreatic cancer BxPC-3 cells at the invasive front in vitro, and promotes tumor growth and invasion in vivo

et al. 2016

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Pancreatic cancer develops dense stromal tissue through the desmoplastic reaction. The aim of the present study was to assess the effects of a fibroblast-rich environment on the malignant potential of pancreatic cancer. Cells from the human pancreatic cancer cell line BxPC-3 were mixed at a ratio of 1:3 (fibroblast-rich) or 1:1 (fibroblast-poor) with cells from the human skin fibroblast line ASF-4-1. In the fibroblast-rich co-culture, tumor budding was observed and BxPC-3 cells were found to be more resistant to gemcitabine than those in the fibroblast-poor co-culture. Immunohistochemistry revealed that the expression of mammalian target of rapamycin was increased at the invasive front of fibroblast-rich co-cultures. In addition, in mouse xenografts of fibroblast-rich co-cultures, tumors were larger and had a higher Ki-67 index compared with that of the fibroblast-poor co-culture xenografts. These results indicate that fibroblast-rich co-cultures may promote the malignant potential of the pancreatic cancer cell line BxPC-3, both in vitro and in vivo.

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Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases

Abstract: Our results provide evidence of dysregulation of the mTOR pathway in penile carcinomas independently of HPV infection. Future clinical studies should further evaluate the prognostic and predictive usefulness of these markers in patients with penile cancer.

Cited by 25 publications

References 16 publications

Identification of somatic gene mutations in penile squamous cell carcinoma

Identification of somatic gene mutations in penile squamous cell carcinoma

High serum CCL20 is associated with tumor progression in penile cancer

ASF-4-1 fibroblast-rich culture increases chemoresistance and mTOR expression of pancreatic cancer BxPC-3 cells at the invasive front in vitro, and promotes tumor growth and invasion in vivo

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