Inhibition of mouse colon cancer growth following immunotherapy with a fraction of hydatid cyst fluid

Cystic Echinococcosis is a cosmopolitan zoonotic disease caused by larval stages of Echinococcus granulosus tapeworm (Moro and Schantz, 2009). Dog or other canines are definitive hosts and herbivores such as sheep are intermediate hosts of this parasite. Humans that considered as accidental intermediate host are infected by ingestion of parasite ova which exist in foods or drinking water especially in vegetables. Following ingestion of eggs, the larval stage of the parasite, called hydatid cyst is formed in intermediate host's viscera especially in liver and lungs. Hydatid cyst wall comprises of an inner cellular layer or germinal epithelium and the outer laminated layer which coat the germinal layer. Germinal layer of a fertile cysts produces brood capsules and protoscolices which may develop into an adult tapeworm if they ingested by a suitable definitive host. The cyst is filled with clear fluid, hydatid cyst fluid, containing molecules of both parasite and host origin (Moro and Schantz, 2009).

Colorectal cancer (CRC) is the third most common cancer in the world after lung cancer and breast cancer. It is also the fourth most common cause of cancer death globally (Torre et al., 2015). In males, CRC is the third most commonly diagnosed cancer worldwide, and in females, it is the second most commonly diagnosed cancer (https://www.iarc.fr/en/media-centre/iarcnews/2010/globocan2008.php.). Also colorectal cancer is the second cause of cancer related death in the united states and about 140,000 new cases occur annually in this country (Siegel et al., 2012, 2017). Surgery is one of the interventions to control this cancer. However, this procedure is less effective against distant metastasis (Gallagher and Kemeny, 2010). Chemotherapy is another method for treatment, However, it has some limitations. So, emphasis has been made on developing immunotherapy for treatment of colorectal cancer. In development of this immunotherapy the lack of tumor specific antigens is the main limitation. Carcino embryonic antigen (CEA)(Thomas et al., 2008) and MUC1(Lindén et al., 2009) are examples of widely studied tumor specific antigens for colorectal cancer immunotherapy. Autologous tumor cell vaccine is another method of immunotherapy in which tumor cells are isolated from patients, engineered in vitro and then injected to the patients. Due to low abundance of tumor specific antigens the efficacy of this method is also poor (Lokhov and Balashova, 2010). Clinical studies also show that this procedure was not able to protect the patients (Sarvizadeh et al., 2019). Although peptide vaccines are used for colorectal cancer immunotherapy, they are poor immunogenic antigens (Bartnik et al., 2012). Dendritic cell vaccines are another approach for cancer immunotherapy. However, according to the clinical trial investigations, results of this method should that it was not efficient (Wooster et al., 2021). DNA vaccines were also used for colorectal cancer immunotherapy. These vaccines are also having poor immunogenicity and none of them have been approved to be used in human (Yang et al., 2014). The mammalian immune system has evolved to respond to infectious microorganisms such as viruses, bacteria, fungi and parasites. So, antigens derived from microorganism are the most immunogenic antigens. Therefore, using infectious agents' antigens which have some degree of homology with cancers (Osinaga, 2007) may compensate disadvantage of poor immunogenicity of cancer derived antigens. These antigens may raise a strong immune response to combat cancer growth and metastasis. In agreement with this concept it has been shown that exposure to cotton dust endotoxin, was inversely related to risk of esophageal and stomach cancers (Wernli et al., 2006). An adverse relationship between some parasite infections and cancers have been reported (Akgül et al., 2003; Plumelle et al., 1997). In an epidemiological study on patients with hydatid cyst, the frequency of cancers was significantly lower than what happens in a normal population (Akgül et al., 2003). Also, it has been shown that some parasites or their products were able to prevent the cancer growths in animal model (Pidherney et al., 1993; Chen et al., 2011; Kallinikova et al., 2001). In this regard, Trypanosoma cruzi has antitumor activity on lymphoma tumors in mice (Mel'nikov et al., 2004). In other study the rate of colon cancer in rats infected with Trypanosoma cruzi, was significantly lower than in non-infected rats (Oliveira et al., 2001). Moreover, it has been shown that immunization with human hydatid cyst fluid inhibits colon cancer growth in mice and that anti –HCF antibodies may play significant role (Berriel et al., 2013).Several studies indicated that there are common antigens between cancers and parasites. Cancers may express mucine type antigens, such as the TF, Tn and sialyl-Tn that play significant role in cell adhesion, metastasis and invasion of malignant cells (Baldus et al., 2004; Casaravilla et al., 2003). Similarly expression of the Tn antigen was shown in adult and larval stages of Echinococcus granulosus (Alvarez et al., 2001). TK antigen which is expressed on the surface of human colorectal carcinoma has also been shown that is present in Mesocestoides vogae, Taenia crassiceps and Taenia hydatigena (Ubillos et al., 2007). Furthermore, preventive effect of Echinococcus granulosus antigens on growth of cancers in animal models has been shown in previous studies (Berriel et al., 2013). Regarding the poor immunogenicity of cancer derived antigens, inhibitory effects of some parasites on cancers growth and existence of share antigens between parasite and cancers, we would attempt to investigate the effect of some hydatid cyst antigens, especially a fraction of hydatid cyst fluid, on the growth of colon cancer in an animal model.

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