Overexpression of α-defensin is associated with bladder cancer invasiveness

Holterman, Daniel A.; Diaz, José I.; Blackmore, Peter F.; Davis, John W.; Schellhammer, Paul F.; Corica, Alberto; Semmes, O. John; Vlahou, Antonia

doi:10.1016/j.urolonc.2005.07.010

Cited by 45 publications

(35 citation statements)

References 17 publications

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“…As members of the CAP family, HNP1-3 are highly similar in regards to bioactivities and are overexpressed in a variety of human tumors (8)(9)(10)(11)(12)(13). In the present study, we showed for the first time that intratumorally expressed HNP1 augments the chemosensitivity of Dox in mouse 4T1 breast cancer.…”

Section: Discussionsupporting

confidence: 57%

“…Among them HNP1-3 possess a high degree of similarity in amino acid sequence and bioactivity. Deregulated expression and secretion of HNP1-3 have been detected in many types of human tumors (8)(9)(10)(11)(12)(13), including lung and breast cancer (12,13). Further investigations have found that tumor cell lines (8) and microdissected fresh tumor cells (10) express HNP1-3.…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

Qin

Wang

et al. 2013

Oncology Reports

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Abstract. Human neutrophil peptides (HNPs) 1-3 possess a high degree of similarity and are deregulated in many types of human tumors. Previous studies have demonstrated that tumor cell lines and microdissected fresh tumor cells express HNP1-3. In vitro, HNP1-3 have been reported to be cytotoxic to various types of tumor cells. Previously, we observed that the intracellular expression of HNP1 increased plasma membrane permeability in A549 cells and inhibited in vivo tumor angiogenesis. Based on these findings, we inferred that the intratumoral expression of HNP1 may benefit chemotherapy in solid tumors. In the present study, we established a mouse 4T1 breast cancer model imitating locally advanced breast cancer (LABC) and we injected the mice intratumorally with plasmid HNP1 (pHNP1). Doxorubicin (Dox) was administered twice i.v. at 5 mg/kg body weight on day 1 and 8. The possible mechanisms were investigated by evaluating cell proliferation and apoptosis, intracellular Dox accumulation, mitochondrial transmembrane potential (ΔΨ m ) and ultrastructural alteration of intratumoral microvessels. Compared with the single agent treatment, the combination of Dox and pHNP1 resulted in a significant delay in in vivo tumor growth and a decrease in lung metastasis. This chemosensitization effect was also observed in an A549 lung cancer model treated with cisplatin (DDP) and pHNP1. MTT assay and Annexin V staining demonstrated that 4T1 cells pre-transfected with pHNP1were significantly more sensitive to Dox, causing increased proliferation inhibition and apoptosis. Further investigations showed that the intracellular expression of HNP1 enhanced Dox accumulation and significantly impaired mitochondrial ΔΨ m . Moreover, in tumor tissues, HNP1 mediated intratumoral microvessel normalization and caused significant in situ tumor cell apoptosis. Our study suggests that intratumoral expression of HNP1 can significantly improve the therapeutic efficacy of Dox in breast cancer, abrogate the influence of multidrug resistance and enhance medication safety. Our findings may be important for the clinical therapeutic strategies of cancer chemotherapy.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

Qin

Wang

et al. 2013

Oncology Reports

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“…It is thought that signals of HNP-1 to HNP-4 originate from tumor-infiltrating leukocytes. It was reported that HNP-1 to HNP-4 can support tumor growth through induction of the epithelial-tomesenchymal transition, thus increasing tumor invasiveness (6,7), as well as through attraction of tumor-associated macrophages that support tumor growth (8).…”

mentioning

confidence: 99%

Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

Vragniau

Hübner

Beidler

et al. 2017

J Virol

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Defensins are small antimicrobial peptides capable of neutralizing human adenovirus (HAdV) in vitro by binding capsid proteins and blocking endosomal escape of virus. In humans, the alpha defensin HD5 is produced by specialized epithelial cells of the gastrointestinal and genito-urinary tracts. Here, we demonstrate, using patient biopsy specimens, that HD5 is also expressed as an active, secreted peptide by epithelial ovarian and lung cancer cells in situ. This finding prompted us to study the role of HD5 in infection and spread of replication-competent, oncolytic HAdV type 3 (HAdV3). HAdV3 produces large amounts of penton-dodecahedra (PtDd), virus-like particles, during replication. We have previously shown that PtDd are involved in opening epithelial junctions, thus facilitating lateral spread of de novo-produced virions. Here, we describe a second function of PtDd, namely, the blocking of HD5. A central tool to prove that viral PtDd neutralize HD5 and support spread of progeny virus was an HAdV3 mutant virus in which formation of PtDd was disabled (mut-Ad3GFP, where GFP is green fluorescent protein). We demonstrated that viral spread of mut-Ad3GFP was blocked by synthetic HD5 whereas that of the wild-type (wt) form (wt-Ad3GFP) was only minimally impacted. In human colon cancer Caco-2 cells, induction of cellular HD5 expression by fibroblast growth factor 9 (FGF9) significantly inhibited viral spread and progeny virus production of mut-Ad3GFP but not of wt-Ad3GFP. Finally, the ectopic expression of HD5 in tumor cells diminished the in vivo oncolytic activity of mut-Ad3GFP but not of wt-Ad3GFP. These data suggest a new mechanism of HAdV3 to overcome innate antiviral host responses. Our study has implications for oncolytic adenovirus therapy. IMPORTANCE Previously, it has been reported that human defensin HD5 inactivates specific human adenoviruses by binding to capsid proteins and blocking endosomal escape of virus. The central new findings described in our manuscript are the following: (i) the discovery of a new mechanism used by human adenovirus serotype 3 to overcome innate antiviral host responses that is based on the capacity of HAdV3 to produce subviral penton-dodecahedral particles that act as decoys for HD5, thus preventing the inactivation of virus progeny produced upon replication; (ii) the demonstration that ectopic HD5 expression in cancer cells decreases the oncolytic efficacy of a serotype 5-based adenovirus vector; and (iii) the demonstration that epithelial ovarian and lung cancers express HD5. The study improves our understanding of how adenoviruses establish infection in epithelial tissues and has implications for cancer therapy with oncolytic adenoviruses.KEYWORDS adenovirus, cancer, defensins, innate immunity

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“…There are reports of increased concentrations of defensins in patients with pyelonephritis (Hiratsuka et al, 2000) or cancer of the bladder (Holterman et al, 2006;Vlahou et al, 2001). We were informed that most of the samples from the CoU were collected from patients after surgery of the lower urinary tract, and we found that the percentage of haematuria was higher in these samples than in the samples sent to the IMMi.…”

mentioning

confidence: 99%

Direct identification of bacteria in urine samples by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and relevance of defensins as interfering factors

Köhling

Bittner

Müller

et al. 2012

Journal of Medical Microbiology

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Overexpression of α-defensin is associated with bladder cancer invasiveness

Cited by 45 publications

References 17 publications

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

Direct identification of bacteria in urine samples by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and relevance of defensins as interfering factors

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