Overexpression of <i>Clostridium perfringens</i> Enterotoxin Receptors Claudin-3 and Claudin-4 in Uterine Carcinosarcomas

Santin, Alessandro D.; Bellone, Stefania; Siegel, Eric R.; McKenney, Jesse K.; Thomas, Maria; Román, Juan José Mora; Burnett, Alexander; Tognon, Germana; Bandiera, Elisabetta; Pecorelli, Sërgio

doi:10.1158/1078-0432.ccr-06-3037

Cited by 33 publications

(19 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other in vivo studies of external therapeutic application of recombinant CPE also reported strong necrosis in the tumor tissues. 33,[35][36][37] In conclusion, we report the successful tumor-targeted CPE gene therapy in vitro and in vivo. This approach efficiently eradicates tumor cells, and provides an attractive therapeutic option for the potential local treatment of refractory solid tumors (including unresectable tumor lesions, residual tumors or recurrences), originating from colon, mammary, pancreas or prostate cancer, which overexpress claudin-3 or -4.…”

Section: Discussionmentioning

confidence: 67%

“…Application of recombinant CPE protein leads to the dose-dependent rapid eradication of claudin-4-or claudin-3-overexpressing pancreas, breast or colon cancer cells in vitro and in vivo. 17,18,[33][34][35][36][37] The intratumoral in vivo application of recombinant CPE did not induce toxinassociated side effects, supporting its great therapeutic potential. However, these approaches require repeated, almost continuous regional or loco-regional application of recombinant CPE at doses ranging from 0.5 to 1.0 mg CPE per application to achieve therapeutic effects.…”

Section: Introductionmentioning

confidence: 76%

“…However, these approaches require repeated, almost continuous regional or loco-regional application of recombinant CPE at doses ranging from 0.5 to 1.0 mg CPE per application to achieve therapeutic effects. 33,36,37 Furthermore, high interstitial pressure in the tumor might hinder proper distribution of externally applied CPE limiting its therapeutic action. 38 Alternatively, intratumoral gene transfer of CPE-expressing vectors could significantly improve duration of toxin availability associated with optimized intratumoral distribution and accumulation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

View full text Add to dashboard Cite

Bacterial toxins are known to be effective for cancer therapy. Clostridium perfringens enterotoxin (CPE) is produced by the bacterial Clostridium type A strain. The transmembrane proteins claudin-3 and -4, often overexpressed in numerous human epithelial tumors (for example, colon, breast, pancreas, prostate and ovarian), are the targeted receptors for CPE. CPE binding to them triggers formation of membrane pore complexes leading to rapid cell death. In this study, we aimed at selective tumor cell killing by CPE gene transfer. We generated expression vectors bearing the bacterial wild-type CPE cDNA (wtCPE) or translationoptimized CPE (optCPE) cDNA for in vitro and in vivo gene therapy of claudin-3-and -4-overexpressing tumors. The CPE expression analysis at messenger RNA and protein level revealed more efficient expression of optCPE compared with wtCPE. Expression of optCPE showed rapid cytotoxic activity, hightened by CPE release as bystander effect. Cytotoxicity of up to 100% was observed 72 h after gene transfer and is restricted to claudin-3-and -4-expressing tumor lines. MCF-7 and HCT116 cells with high claudin-4 expression showed dramatic sensitivity toward CPE toxicity. The claudin-negative melanoma line SKMel-5, however, was insensitive toward CPE gene transfer. The non-viral intratumoral in vivo gene transfer of optCPE led to reduced tumor growth in MCF-7 and HCT116 tumor-bearing mice compared with the vector-transfected control groups. This novel approach demonstrates that CPE gene transfer can be employed for a targeted suicide gene therapy of claudin-3-and -4-overexpressing tumors, leading to the rapid and efficient tumor cell killing in vitro and in vivo.

show abstract

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

View full text Add to dashboard Cite

show abstract

“…There is a growing body of evidence suggesting that alterations in CLDN expression may be involved in the progression of some cancers (17) such as endometrial carcinoma (11). However, the regulation of these changes in expression are not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, increases in CLDN-3 and -4 expression have been observed in uterine serous papillary carcinoma (11,12), clear-cell endometrial carcinoma (11) and uterine carcinosarcoma (13). Notably, overexpression of CLDN-3 and -4 was associated with a poor clinical outcome (12).…”

Section: Introductionmentioning

confidence: 99%

Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells

Cuevas

Gaska

Gist

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Endometrial cancer is the most common female reproductive cancer in the United States and is associated with deregulated tight junction protein expression. Given the highly estrogen-responsive nature of this tissue, we investigated the effects of estrogen and its agonist, 4-OH TAM, on the expression and subcellular localization of the tight junction protein claudin-4 (CLDN-4), in HEC-1A endometrial cancer cells. In untreated HEC-1A cells, we observed dramatic overexpression of claudin-4 protein. In addition, differential detergent extraction analysis indicated that claudin-4 was localized primarily in the membrane but also found in the cytosolic, nuclear and cytoskeletal fractions. Upon exposure of HEC-1A to estradiol (E 2 ), we observed a biphasic effect both on the overall expression of claudin-4 protein and on its cytosolic and cytoskeletal presence as demonstrated by immunoblot analysis. Immunofluorescence analysis also revealed a biphasic effect of E 2 on claudin-4 expression. In contrast, we observed no changes in expression levels nor in the subcellular distribution patterns of claudin-4 in HEC-1A cells treated with different concentrations of 4-OH TAM. The intracellular presence of CLDN-4 coupled with the biphasic effects of E 2 on CLDN-4 expression in the cytoskeleton suggest that this protein may be involved in cell signaling to and from TJs.

show abstract

Targeting claudin‐overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin

et al. 2020

View full text Add to dashboard Cite

Clostridium perfringens enterotoxin (CPE) can be used to eliminate carcinoma cells that overexpress on their cell surface CPE receptorsa subset of claudins (e.g., Cldn3 and Cldn4). However, CPE cannot target tumors expressing solely CPE-insensitive claudins (such as Cldn1 and Cldn5). To overcome this limitation, structure-guided modifications were used to generate CPE variants that can strongly bind to Cldn1, Cldn2 and/or Cldn5, while maintaining the ability to bind Cldn3 and Cldn4. This enabled (a) targeting of the most frequent endocrine malignancy, namely, Cldn1-overexpressing thyroid cancer, and (b) improved targeting of the most common cancer type worldwide, non-small-cell lung cancer (NSCLC), which is characterized by high expression of several claudins, including Cldn1 and Cldn5. Different CPE variants, including the novel mutant CPE-Mut3 (S231R/S313H), were applied on thyroid cancer (K1 cells) and NSCLC (PC-9 cells) models. In vitro, CPE-Mut3, but not CPEwt, showed Cldn1dependent binding and cytotoxicity toward K1 cells. For PC-9 cells, CPE-Mut3 improved claudin-dependent cytotoxic targeting, when compared to CPEwt. In vivo, intratumoral injection of CPE-Mut3 in xenograft models bearing K1 or PC-9 tumors induced necrosis and reduced the growth of both tumor types. Thus, directed modification of CPE enables eradication of tumor entities that cannot be targeted by CPEwt, for instance, Cldn1overexpressing thyroid cancer by using the novel CPE-Mut3.

show abstract

Overexpression of Clostridium perfringens Enterotoxin Receptors Claudin-3 and Claudin-4 in Uterine Carcinosarcomas

Cited by 33 publications

References 15 publications

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells

Targeting claudin‐overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin

Contact Info

Product

Resources

About