The Rho-activating CNF1 toxin from pathogenic E. coli: A risk factor for human cancer development?

Infectious Agents and Cancer The Rho-activating CNF1 toxin from pathogenic E. coli: A risk factor for human cancer development? Sara Travaglione 0 Alessia Fabbri 0 Carla Fiorentini 0 0 Address: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita, viale Regina Elena 299 , 00161-Rome , Italy Nowadays, there is increasing evidence that some pathogenic bacteria can contribute to specific stages of cancer development. The concept that bacterial infection could be involved in carcinogenesis acquired a widespread interest with the discovery that H. pylori is able to establish chronic infections in the stomach and that this infection is associated with an increased risk of gastric adenocarcinoma and mucosa associated lymphoid tissue lymphoma. Chronic infections triggered by bacteria can facilitate tumor initiation or progression since, during the course of infection, normal cell functions can come under the control of pathogen factors that directly manipulate the host regulatory pathways and the inflammatory reactions. Renowned publications have recently corroborated the molecular mechanisms that link bacterial infections, inflammation and cancer, indicating certain strains of Escherichia coli as a risk factor for patients with colon cancer. E. coli is a normal inhabitant of the human intestine that becomes highly pathogenic following the acquisition of virulence factors, including a protein toxin named cytotoxic necrotizing factor 1 (CNF1). This toxin permanently activates the small GTP-binding proteins belonging to the Rho family, thus promoting a prominent polymerization of the actin cytoskeleton as well as a number of cellular responses, including changes in protein expression and functional modification of the cell physiology. CNF1 is receiving an increasing attention as a putative factor involved in transformation because of its ability to: (i) induce COX2 expression, an immediate-early gene over-expressed in some type of cancers; (ii) induce a long-lasting activation of the transcription factor NF-kB, a largely accepted marker of tumor cells; (iii) protect epithelial cells from apoptosis; (iv) ensue the release of pro-inflammatory cytokines in epithelial and endothelial cells; and (v) promote cellular motility. As cancer may arise through dysfunction of the same regulatory systems, it seems likely that CNF1-producing E. coli infections can contribute to tumor development. This review focuses on the aspects of CNF1 activity linked to cell transformation with the aim of contributing to the identification of a possible carcinogenic agent from the microbial world. - Introduction Bacterial infection and cancer In the last century, cancer research thoroughly established the role of major carcinogenic agents of different nature, including infectious agents. However, although there is a general agreement that some viruses, such as hepatitis B virus (HBV), Epstein-Barr virus (EBV) and human papilloma virus (HPV) can cause cancer, the involvement of bacteria in carcinogenesis remains controversial. The role of viral infections in tumor onset is widely accepted because of the direct action of single viral genes (oncogenes) that result in cell transformation [1]. By contrast, the molecular mechanism(s) by which bacteria might promote tumorigenesis are still poorly characterized. Hence, one of the main challenges, nowadays, is to define the impact of bacterial infections as a cause of cancer and eventually design strategies for their prevention and control. Bacterial infections are usually believed to cause acute diseases, but it is now becoming clear that some bacteria can contribute to the establishment of chronic diseases, including cancer [2]. The concept that bacterial infection could be involved in carcinogenesis was first proposed in the late nineteenth and early twentieth centuries, based on the discovery of bacteria at the sites of tumors, although there was no proof that the bacteria were in any way causative [3]. Since then, the putative link between chronic infection and cancer acquired a widespread interest with the discovery that Helicobacter pylori is able to establish chronic infections in the stomach and that this infection is associated with an increased risk of gastric adenocarcinoma [4] and mucosa associated lymphoid tissue (MALT) lymphoma [5]. In this context, it is worth noting that H. pylori is classified as a class I carcinogenic factor [6]. Other chronic bacterial infections have been linked to human carcinogenesis although the underlying mechanisms remain to be defined (reviewed in [2]). The strongest epidemiological case is for Salmonella enterica serovar typhi (S. typhi), the agent of typhoid, which can also lead to chronic bacterial carriage in the gallbladder [7-11]. Surveys of typhoid outbreaks have shown that those who become carriers have an increased risk of developing hepatobiliary carcinoma compared with people who have had acute typhoid and have cleared the infection [9]. A recurring theme in the link between bacterial infection and carcinogenesis is that of chronic inflammation, which is often a common feature of persistent infection [2,12]. One of the key molecules that link chronic inflammation and cancer is represented by the NF-kB family of transcription factors [12,13]. In particular, different mouse studies provide strong and direct genetic evidence that the classical, IKK- dependent NF-kB activation pathway is indeed a crucial mediator of tumor promotion [14-16]. This pathway is triggered by bacterial and viral infections, as well as by pro-inflammatory cytokines, such as TNF- and IL-1, all of which activate the IKK complex [17]. This complex phosphorilates the NF-kB inhibitors IkBs, thereby targeting them for proteosomal degradation and freeing NF-kB to enter the nucleus and mediate transcription of target genes. It is worth noting that many of the genes able to mediate alterations characterizing a tumor cell are under the transcriptional control of NF-kB (reviewed in [18,19]). For example, the activity and expression of cyclin D1, CDK2 kinase, c-myc, p21, p53 and pRb, which are involved in the control of cell cycle and are altered in several types of cancer, are NF-kB-dependent. The expression of numerous cytokines, that are growth factors for tumor cells (IL-1, TNF, IL-6, EGF) are also regulated by NF-kB. Tissue invasion and metastasis, two crucial events of tumor progression, are regulated by NF-kB-dependent genes, including metalloproteases (MMPs), urokinase type of plasminogen activator (uPA), IL-8, the adhesion molecules VCAM-1, ICAM-1 and ELAM-1. NF-kB is also involved in the regulation of angiogenesis, the process by which tumor cells promote neo-vascularization. Finally, altered expression of genes involved in suppression of apoptosis (i.e. Bcl-2 family members and IAP proteins), a key feature of cancer cells, is often due to deregulated NFkB activity. Concerning this last poin (...truncated)