Cyclooxygenase-2 Expression in Primary and Metastatic Merkel Cell Carcinoma

Joachims, Zohar; Feinmesser, Raphael; Purim, Ofer; Halpern, Marisa; Brenner, Baruch; Fenig, Eyal; Roizman, Pepi; Sulkes, Jaqueline; Feinmesser, Meora

doi:10.1097/pai.0b013e31815f982a

Cited by 5 publications

(4 citation statements)

References 18 publications

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“…The expression of COX-2 mRNA and protein is elevated in various human malignancies, which may play a critical role in the development of cancer [16][17][18]. Our study showed that the positive rate of COX-2 expression in human NSCLC was significantly higher than that in the matched normal NSCLC tissue.…”

Section: Discussionmentioning

confidence: 57%

Prognostic significance of VEGF-C expression in correlation with COX-2, lymphatic microvessel density, and clinicopathologic characteristics in human non-small cell lung cancer

Guo¹,

Chen²,

Xu³

et al. 2009

ABBS

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Section: Discussionmentioning

confidence: 57%

Prognostic significance of VEGF-C expression in correlation with COX-2, lymphatic microvessel density, and clinicopathologic characteristics in human non-small cell lung cancer

Guo¹,

Chen²,

Xu³

et al. 2009

ABBS

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“…The prostaglandin synthesis pathway investigated in this study represents a promising avenue for targeted MCC therapy. COX-2 expression is detected in 77% of primary MCC tumors, and its welldocumented overexpression has been shown to promote tumorigenesis [28,30]. Both COX-1 and COX-2 enzymes are responsible for converting arachidonic acids into prostaglandin H2 (PGH2), which serves as a precursor for various prostaglandins (PGD2, PGE2, PGF2, PGI2) and thromboxane A2 (TXA2) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Stem cells that lack COX-2 expression tend to be less aggressive and better differentiated. A study found that 77% of primary MCC tumors express COX-2 and it was related to a high mitotic rate, a characteristic of aggressive tumor behavior [30].…”

Section: Cyclooxygenase (Cox)-2 Overexpression and Upregulation Of Pr...mentioning

confidence: 99%

The effect of selinexor on prostaglandin synthesis in virus-positive Merkel cell carcinoma cell lines

Narayanan,

Bartley,

Landes

et al. 2024

Arch Dermatol Res

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Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways.To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway.Protein expression was determined through immunoblotting and quanti ed by densitometric analysis.Statistical signi cance was determined with t-test.Treatment of MCPyV-infected cell lines with selinexor resulted in a signi cant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our ndings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.

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“…The molecular changes in MCC development are not well-characterized [120]. Similar to neuroendocrine carcinomas, most primary and metastatic MCC express COX-2 at rather low to moderate levels [121,122]. Studies in experimental animal models or cell cultures addressing the issue of PG signaling are missing.…”

Section: Merkel Cell Carcinomamentioning

confidence: 95%

Cyclooxygenase-dependent signaling is causally linked to non-melanoma skin carcinogenesis: pharmacological, genetic, and clinical evidence

Müller‐Decker

2011

Cancer Metastasis Rev

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Cyclooxygenase (COX)-derived prostaglandins (PGs) exhibit manifold functions in acute and chronic skin inflammation induced by a number of physical (ultraviolet (UV) light, wounding) and chemical (12-O-tetradecanoylphorbol 13-acetate (TPA), arachidonic acid) noxious stimuli. Depending on the challenge and the context, constitutively expressed COX-1 or the transiently induced COX-2 isoform are of relevance. Moreover, squamous cell carcinoma (SCC) of skin is a prominent example of epithelial neoplasia that consistently overexpresses COX-2 in the parenchyme and the mesenchyme of premalignant and malignant lesions, while COX-1 expression remains unaltered. Pharmacological, clinical, and experimental animal studies as well as a few epidemiological studies document the importance of PG signaling in non-melanoma skin cancer including SCC and basal cell carcinoma (BCC) in humans and mice. Increased levels of PGE(2) and PGF(2α) in premalignant and/or malignant epithelial skin cancers are due to the constitutive upregulation of enzymes involved in PG biosynthesis, such as COX-2, and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), which is involved in the inactivation of PG, thus counteracting the activities of COX. Most remarkably, genetic studies show that mice which are deficient in COX-2 or COX-1 are protected from the development of SCC when applying the multi-stage chemical carcinogenesis protocol. Conversely, the forced overexpression of COX-2 in the proliferative basal compartment of the stratified skin epidermis results in spontaneous hyperplasia and dysplasia in transgenic mice and furthermore a sensitization for cancer development by conferring an auto-promoted skin phenotype. In multi-stage carcinogenesis, it also becomes clear that aberrant COX-2 overexpression and activity are causally involved in tumor promotion and tumor progression rather than initiation. In contrast, using as inducer of carcinogenesis the complete carcinogen UV B light, depletion of COX-2 but not of COX-1 makes mouse skin resistant for SCC, indicating that here, only COX-2 is essential. Depending on the type of challenge, COX-2-dependent signaling contributes to the pre-invasive growth of the skin epidermis by a delayed onset of terminal differentiation, or stimulation of hyperproliferation and survival. With respect to BCC, the genetic ablation of COX-2 but also of COX-1 leads to a strongly reduced tumor burden in the skin of Patched (Ptch)1(+/-) mice, which due to the deletion of a Ptch1 allele, spontaneously develop BCC resembling human familial basal cell nevus syndrome and sporadic BCC. Nonsteroidal anti-inflammatory drugs and the COX-2-selective inhibitors (COXibs) exhibit impressive efficacy inhibiting tumor burden in various mouse models of SCC and BCC. Most importantly, in humans the interruption of COX-2 signaling is an effective strategy to treat and chemo-prevent non-melanoma skin cancer in individuals who are at high risk for the disease. However, any potential beneficial effect of...

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Cyclooxygenase-2 Expression in Primary and Metastatic Merkel Cell Carcinoma

Cited by 5 publications

References 18 publications

Prognostic significance of VEGF-C expression in correlation with COX-2, lymphatic microvessel density, and clinicopathologic characteristics in human non-small cell lung cancer

Prognostic significance of VEGF-C expression in correlation with COX-2, lymphatic microvessel density, and clinicopathologic characteristics in human non-small cell lung cancer

The effect of selinexor on prostaglandin synthesis in virus-positive Merkel cell carcinoma cell lines

Cyclooxygenase-dependent signaling is causally linked to non-melanoma skin carcinogenesis: pharmacological, genetic, and clinical evidence

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