Penile cancer

Thomas, Anita C; Necchi, Andrea; Muneer, Asıf; Tobias-Machado, Marcos; Tran, Anna; Rompuy, Anne‐Sophie Van; Spiess, Philippe E.; Albersen, Maarten

doi:10.1038/s41572-021-00246-5

Cited by 110 publications

(99 citation statements)

References 239 publications

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“…High-risk (HR) HPV infections, especially HPV-16 infections, respond for approximately 30% of PeC cases [ 30 ], and may be prevented by vaccination. The role of HR-HPV E6 and E7 proteins in the deregulation of pRB and p53 leading to PeC has been investigated [ 7 , 8 ]. Nevertheless, other genes, proteins, and pathways functionally deregulated in non-HPV-associated PeC have also been explored, including EGFR [ 31 ], Wnt [ 32 ], MAPK/ERK, and PI3K-AKT-mTOR pathways [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, almost half of the patients are still submitted to bilateral inguinal lymphadenectomy which is accompanied by complications in two thirds of the cases [ 5 , 6 ]. Some risk factors have been described in PeC etiology, including poor penile hygiene, low socioeconomic status, phimosis, chronic inflammation, tobacco use, immunosuppression, and human papillomavirus (HPV) infection [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Genes and molecular pathways altered in penile carcinogenesis include: (i) the expression of high-risk HPV E6 and E7 genes, whose products interfere respectively with P53 and pRb; (ii) MAPK/ERK pathway and (iii) PI3K-AKT-mTOR axis [ 7 , 8 ]. In summary, penile carcinogenesis is driven by both HPV-dependent and HPV-independent pathways [ 7 ]. Recently, epigenetic factors have gained attention.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Furuya

Murta

Carrasco

et al. 2021

Cancers

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Penile cancer (PeC) carcinogenesis is not fully understood, and no biomarkers are reported in clinical practice. We aimed to investigate molecular signatures based on miRNA and mRNA and perform an integrative analysis to identify molecular drivers and pathways for PeC development. Affymetrix miRNA microarray was used to identify differentially expressed miRNAs (DEmiRs) comparing 11 tumoral tissues (TT) paired with non-neoplastic tissues (NNT) with further validation in an independent cohort (n = 13). We also investigated the mRNA expression of 83 genes in the total sample. Experimentally validated targets of DEmiRs, miRNA-mRNA networks, and enriched pathways were evaluated in silico. Eight out of 69 DEmiRs identified by microarray analysis were validated by qRT-PCR (miR-145-5p, miR-432-5p, miR-487b-3p, miR-30a-5p, miR-200a-5p, miR-224-5p, miR-31-3p and miR-31-5p). Furthermore, 37 differentially expressed genes (DEGs) were identified when comparing TT and NNT. We identified four downregulated DEmiRs (miR-30a-5p, miR-432-5p, miR-487b-3p, and miR-145-5p) and six upregulated DEGs (IL1A, MCM2, MMP1, MMP12, SFN and VEGFA) as potential biomarkers in PeC by their capacity of discriminating TT and NNT with accuracy. The integration analysis showed eight dysregulated miRNA-mRNA pairs in penile carcinogenesis. Taken together, our findings contribute to a better understanding of the regulatory roles of miRNAs and altered transcripts levels in penile carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Furuya

Murta

Carrasco

et al. 2021

Cancers

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“…According to two population-based cancer registry surveys, the survival of PeCa patients has not improved in Europe or the United States in the last three decades [3,4]. Although ongoing preclinical studies show promising results for more personalized therapy, the lack of improvement in survival is probably due to delayed diagnosis and lack of advances in curative standardized treatment options (reviewed in [5]). In the present study, we established and characterized five penile cancer-derived cells from cancer tissues (two epithelial and three CAFs).…”

Section: Introductionmentioning

confidence: 99%

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies

Kuasne

Canto

Aagaard

et al. 2021

Cells

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Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K/AKT/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease.

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“…The prognosis for patients with early stage PSCC is good but worsens with the presence and extent of lymph node metastases (5). Patients with advanced disease have limited treatment options and current cisplatin-based chemotherapy regimens offer poor and non-durable response rates with high toxicity (6,7). Therefore, there is an unmet need for novel systemic therapeutic strategies that are both effective and tolerable (7).…”

Section: Introductionmentioning

confidence: 99%

Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor

et al. 2021

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Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV− tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV− cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.

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Penile cancer

Cited by 110 publications

References 239 publications

Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies

Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor

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