Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer

Cocco, Emiliano; Casagrande, Francesca; Bellone, Stefania; Richter, C.; Bellone, Marta; Todeschini, Paola; Fu, Han; Montagna, Michele K.; Mor, Gil; Schwartz, Peter E.; Arin-Silasi, Dan; Azoudi, Masoud; Rutherford, Thomas J.; Abu-Khalaf, Maysa; Pecorelli, Sërgio; Santin, Alessandro D.

doi:10.1186/1471-2407-10-349

Cited by 39 publications

(50 citation statements)

References 16 publications

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“…Earlier, Cocco et al showed similar results using a fluorescein isothiocyanate-conjugated cCPE in models of ovarian cancer (15). However, the direct clinical translation of optical imaging approaches is limited by penetration depth of light, which is less than a couple of millimeters.…”

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confidence: 80%

Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer

et al. 2015

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The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C-terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate wholebody quantitative SPECT imaging of preneoplastic breast cancer tissue using 111 In-labeled cCPE. Methods: cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow 111 In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4-expressing MDA-MB-468 and SQ20b cells, compared with claudin-4-negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4-expressing breast cancer lesions. Results: The uptake of 111 In-cCPE.GST in claudin-4-positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in 111 In-GST or claudin-4-negative HT1080 tumors (6.72 ± 0.18 vs. 3.88 ± 1.00 vs. 2.36 ± 1.25 percentage injected dose per gram [%ID/g]; P , 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4-positive, and 111 In-cCPE.GST uptake was 3.2 ± 0.70 %ID/g, significantly higher than 111 In-GST (1.00 ± 0.60 %ID/g; P , 0.05). Mammary fat pads in mice aged 80 d bore claudin-4-positive aplastic lesions and accumulated 111 In-cCPE.GST (3.17 ± 0.51 %ID/g) but not 111 In-GST (0.99 ± 0.39 %ID/g; P , 0.001). Conclusion: Taken together, 111 In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer.

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confidence: 80%

Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer

et al. 2015

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“…Several studies have used the C-terminal fragment of CPE, fused with various cytotoxic drugs, to specifically kill tumor cells expressing claudin-3 and claudin-4 (16,49,50,52). This approach has also been successfully employed to target chemotherapy-resistant ovarian carcinomas or to reduce the formation of B16 melanoma cell-derived lung metastases (4,41). Based on these observations and our findings, we speculate that blocking peptides or neutralizing antibodies raised to the first extracellular loop of claudin-2 may be employed to limit the dissemination of cancer cells to the liver.…”

Section: Fig 10mentioning

confidence: 99%

“…Claudin-3 and claudin-4 are overexpressed in a range of human epithelial cell-derived tumors, including breast, prostate, ovarian, and pancreatic cancers (4). Interestingly, these tightjunctional proteins are bound by the Clostridium perfringens enterotoxin (CPE), which interacts with the second extracellular loop of claudin-3 (9).…”

Section: Fig 10mentioning

confidence: 99%

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

Tabariès

Dupuy

Dong

et al. 2012

Molecular and Cellular Biology

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hWe previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. Metastatic tumor cells must overcome numerous barriers in order to successfully disseminate to distant organs. The metastatic cascade consists of multiple steps, including local tumor cell migration, invasion and intravasation into the lymphatic system or bloodstream, survival in the circulation, adhesion/extravasation at the metastatic site, evasion of immunosurveillance, and eventual growth in a foreign microenvironment (29,30). Of these numerous steps, interactions between tumor cells and resident cells within the metastatic microenvironment represent the most important determinants contributing to the ability of cancer cells to metastasize to specific organs (14,24).The liver represents a common site of metastasis for solid cancers and represents the third most common site for breast cancer metastasis (12). Unique structural features of the liver, including the open fenestrae that characterize the sinusoidal endothelium coupled with the lack of an organized subendothelial basement membrane, have a great impact on tumor interactions within the hepatic microenvironment. Early in vivo electron microscopy studies revealed that breast cancer cells, upon seeding the liver, can extend cellular projections through the fenestrated endothelium into the space of Disse, making direct contact with hepatocytes (36). Subsequent in vitro studies revealed that breast cancer cells form electron-dense structures at points of contact between hepatocytes, which are reminiscent of tight-junctional complexes (37). The importance of cancer cell-hepatocyte interactions has been reinforced by the observation that colorectal cancer cells also interact directly with hepatocytes during liver metastasis (31, 32). However, the mechanisms underlying these heterotypic cell-cell interactions are largely unexplored.Claudins are key components within tight junctions, and they participate in homo-and hete...

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“…In addition to pancreatic cancer, claudin-4 is a potential target in chemotherapy-resistant ovarian cancer and other highly aggressive human epithelial tumors including breast and prostate cancer, making it attractive as a molecular imaging target. [23, 24] Moreover, targeting claudin-4 for therapy of PDAC was the subject of a recent review by Kojima et al and a number of studies describing claudin-4 as a target for molecular imaging have recently been reported. [25] Neesse et al assessed the ability of a naturally occurring peptide ligand for claudin-4 to detect tumors that overexpress claudin-4.…”

Section: Tumor Epithelial Cellsmentioning

confidence: 99%

Challenges of Pancreatic Cancer

Dimastromatteo¹,

Houghton²,

Lewis³

et al. 2015

The Cancer Journal

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The development of novel molecular cancer imaging agents has considerably advanced in recent years. Numerous cancer imaging agents have demonstrated remarkable potential for aiding the diagnosis, staging, and treatment planning at the preclinical stage which in turn has led to a number of agents being approved for human trials. Pancreatic ductal adenocarcinoma (PDAC) is currently the most deadly common carcinoma with an overall 5-year survival rate of about 6%. As detection technologies progress, the need for molecular imaging tools that will allow the diagnosis at an early stage will be crucial to improving patient outcomes. In this review, we will highlight agents that illuminate various cell populations that comprise the tumor: epithelial, endothelial, and stromal tumor cells.

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Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer

Cited by 39 publications

References 16 publications

Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer

Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

Challenges of Pancreatic Cancer

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