Claudins Overexpression in Ovarian Cancer: Potential Targets for Clostridium Perfringens Enterotoxin (CPE) Based Diagnosis and Therapy

Abstract

Claudins are a family of tight junction proteins regulating paracellular permeability and cell polarity with different patterns of expression in benign and malignant human tissues. There are approximately 27 members of the claudin family identified to date with varying cell and tissue-specific expression. Claudins-3, -4 and -7 represent the most highly differentially expressed claudins in ovarian cancer. While their exact role in ovarian tumors is still being elucidated, these proteins are thought to be critical for ovarian cancer cell invasion/dissemination and resistance to chemotherapy. Claudin-3 and claudin-4 are the natural receptors for the Clostridium perfringens enterotoxin (CPE), a potent cytolytic toxin. These surface proteins may therefore represent attractive targets for the detection and treatment of chemotherapy-resistant ovarian cancer and other aggressive solid tumors overexpressing claudin-3 and -4 using CPE-based theranostic agents.

Clostridium perfringens enterotoxin C‐terminal domain labeled to fluorescent dyes for in vivo visualization of micrometastatic chemotherapy‐resistant ovarian cancer

“…Remarkably, although the systemic administration of the full length CPE in mice is toxic, limiting its use to local therapies, the injection of the carboxy-terminal fragment (i.e., the c-terminal 30aa, c-CPE) is devoid of any toxicity while preserving the binding affinity to the receptors 16 . Therefore, the use of c-CPE as a carrier for diagnostic/real-time imaging contrast agents or for therapeutics can represent a novel approach for the potential detection/treatment of Claudin-3/4 overexpressing ovarian tumors 19 .…”

Clostridium perfringens enterotoxin

“…Results from several lab studies have supported that hypothesis [93][94][95][96][97][98]. For example, pancreatic, prostate, and breast carcinoma cancer cells expressing high levels of claudin CPE receptors were found to be highly sensitive to the enterotoxin in vitro.…”

The interaction of Clostridium perfringens enterotoxin with receptor claudins

“…A final translational field where knowledge of CPE binding interactions is being exploited concerns cancer therapy and diagnosis [16,70]. Many fatal cancers are derived from epithelial tissues and claudins are often overexpressed in those cancers.…”

“…Tumor cells over-expressing claudin-4 are highly sensitive to CPE in vitro . Direct injection of CPE into tumors can reduce tumor volume significantly [16,71]. As an alternative approach, C-CPE has been coupled with other cytotoxic proteins to obtain potent killing properties against tumors expressing claudin receptors for CPE [16,70–72].…”