Encyclopedia
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Mehdi Shakibaei.
Colorectal cancer (CRC) is one of the most common tumors worldwide, with a higher rate of distant metastases than other malignancies and with regular occurrence of drug resistance. Therefore, scientists are forced to further develop novel and innovative therapeutic treatment strategies, whereby it has been discovered microorganisms, albeit linked to CRC pathogenesis, are able to act as highly selective CRC treatment agents. Consequently, researchers are increasingly focusing on bacteriotherapy as a novel therapeutic strategy with less or no side effects compared to standard cancer treatment methods. With multiple successful trials making use of various bacteria-associated mechanisms, bacteriotherapy in cancer treatment is on its way to become a promising tool in CRC targeting therapy.
- colorectal cancer
- biotherapeutical toxins
- bacteriocins
- bacterial peptides
- bacteriotherapy
- microbiota
1. Introduction
Colorectal cancer (CRC) is globally among the most common causes of cancer-related death, whereby 50% of patients who are not showing metastasis when diagnosed, will develop metastases with the progressing course of the cancer disease [1,2,3,4][1][2][3][4], with the most common sites being liver and lungs [3]. CRC is known to be affected by environmental and lifestyle factors including poor diet, physical inactivity and a sedentary lifestyle [5,6][5][6]. The pathogenesis of CRC is characterized by multiple factors contributing to the disease, such as genetic mutations and epigenetic alterations as well as building of and interaction with the tumor microenvironment (TME) that promotes further tumor progression and metastasis [7,8,9][7][8][9]. Hereby, chronic inflammation, known as a risk factor for CRC development, plays a pivotal role, since diverse pro-inflammatory mediators such as cytokines, chemokines, carcinogens, chemotherapeutic substances or radiation, have been demonstrated to further stimulate inflammatory pathways (e.g., nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells, NF-κB), leading to tumor cell proliferation and invasion [10,11,12,13][10][11][12][13]. Moreover, it has been frequently shown that inflammatory bowel diseases and bowel-linked inflammation are not uncommonly associated with CRC tumor progression, highlighting the role of the gut’s inflammation-protective capability [14].
The gut, as a tissue hosting approximately 3 × 1013 colonic bacteria, is assumed to be responsible for the majority of known microbial immunomodulatory effects and immunity in the intestinal tract as well as for metabolism and inflammation and even shows cancer-protective properties [15,16,17,18,19][15][16][17][18][19]. This effect has already been discovered in the late 1800 s by William B. Coley, who was able to demonstrate tumor reduction and extended survival of CRC patients by using a mix of bacterial species Serratia marcescens and Streptococcus pyogenes for the treatment of sarcomas [20].
Today, bacterial therapy has been rediscovered as a potential treatment strategy for CRC [18,21,22,23][18][21][22][23], especially because tumor cells are capable of genetic mutations, and are thus able to escape from immune monitoring and can even develop resistance to standard immunotherapies. Moreover, current anti-tumor therapeutics are associated with high toxicity to normal cells, finally leading to severe side effects in patients, thus current cancer treatment is frequently exposed to a number of drawbacks [16,24,25][16][24][25]. Therefore, using bacteria strains possessing anti-cancer properties represents a promising strategy as preventative, concomitant or alternative treatment of CRC [18,20,21,22,23][18][20][21][22][23].
In particular, bacterial peptides, including toxins, show characteristics such as low molecular weight and hydrophobicity, facilitating their entry into tumor tissue, where they can unfold their anti-cancer effects [26]. Furthermore, taking advantage of the fact that some bacteria show tumor targeting specificity, they have also been used as carriers for anti-tumor agents and even for tumor and metastases detection in previous studies [27,28,29,30,31][27][28][29][30][31]. Besides, using bacteria as probiotics has been presented as another application strategy in the treatment of CRC and its prevention, showing direct effects by suppressing carcinogens and stimulating immune modulation [32,33,34,35][32][33][34][35]. This demonstrates again the various methods of bacterial application in CRC treatment approaches and its anti-cancer potential on various levels.
2. Bacteriotherapy in CRC Treatment
In recent decades, the mortality rate of various cancers has remarkably increased, forcing scientists to further develop novel and innovative therapeutic treatment strategies, whereby bacterial therapy has been shown to be a very promising one [36], especially regarding CRC, which ranks among the most prevalent life-threatening types of cancer, bacteriotherapy provides an attractive novel and cost-efficacious treatment approach. Accordingly, research has shown that the microbiome of patients suffering from CRC has a significantly different composition than that of healthy individuals [37,38][37][38]. Moreover, it is known that pathogenic bacteria and microorganisms can greatly contribute to the development of CRC, but on the other hand, others were found to act as effective therapeutic agents with less or even no side effects compared to standard cancer treatment [20,39][20][39]. Based on this background further research on bacteria’s role in the treatment of patients suffering from CRC appears to be very promising.2.1. Mechanisms Used in Bacteriotherapy in CRC
There have been several mechanisms of bacteria described to date that researchers are taking advantage of in the treatment of CRC via bacteriotherapy, such as formation of pores in the cell membrane, inhibition of metastasis, tumor necrosis or apoptosis [20,40][20][40]. In particular, apoptosis has been known as a key goal in cancer treatment for several decades in order to eradicate tumor tissue that is characterized by a loss of balance between cell proliferation and death [41,42][41][42]. The term apoptosis or programmed cell death, describes a very complex process, which includes various pathways and mechanisms (Figure 1) [42,43][42][43]. In general, it is distinguished between the intrinsic (mitochondrial-dependent) pathway and the extrinsic (receptor-dependent) pathway, both finally leading to Caspase activity and apoptosis. Programmed cell death, stimulated by the intrinsic pathway, is characterized by cytochrome c release from pro-apoptotic proteins (B-cell lymphoma 1-Bcl-1, Bcl-2-associated X protein-Bax, Bcl-2-Antagonist of Cell Death-Bad and BCL2 Antagonist/Killer 1-Bak)-stimulated mitochondria from the intermembrane space into the cytosol, subsequently forming the apoptosome complex together with Caspase-9, eventually leading to apoptosis. The extrinsic pathway on the other hand is stimulated by cell membrane death receptors such as Tumor necrosis factor receptor (TNF-R) binding to natural ligands, whereby initiator Caspase-8 is induced, which promotes cleavage of further downstream caspases, finally inducing apoptosis [41,42,44,45][41][42][44][45]. Moreover, receptor-ligand binding induces several cellular responses, including the activation of NF-κB, which can activate pro-apoptotic proteins depending on the cellular context [44,45][44][45]. However, the two main apoptotic pathways must not be considered separately, since previous research showed that they are linked with each other and metabolites of one pathway can have an impact on the other [45].
Figure 1. Schematic diagram showing the mechanisms of apoptosis triggered by bacterial peptides in cancer cells. (A) Bacterial toxins, secreted by various bacterial strains can cause apoptosis via the mitochondria-dependent pathway by causing cell injury, for example, by cell membrane pore formation. Induction of the intrinsic pathway leads to activation of pro-apoptotic proteins (Bcl-1, Bad, Bax, Bak), which in turn stimulates the release of cytochrome c molecules from the mitochondrial intermembrane space into the cytosol. Cytochrome c, together with Caspase-9 forms a complex called the “apoptosome”, finally stimulating executioner caspases (e.g., Caspase-3) leading to cancer cell apoptosis. (B) Bacterial proteins and peptides can have a modulatory impact on cytokines such as TNF-α, resulting in activation or blockage of NF-κB. With suppression of NF-κB, which stimulates anti-apoptotic proteins Bcl-2 and Bcl-xL, which in turn regulates apoptosis by blocking cytochrome c release, pro-apoptotic Bax and Bak-proteins remain stimulated and apoptosis is induced. (C) Besides stimulating the intrinsic pathway of apoptosis, probiotics are capable of apoptosis induction through stimulation of the extrinsic receptor-dependent pathway. Here, so called cell death receptors, such as TNF-R, bind to natural ligands, whereby initiator Caspase-8 and -10 are activated to cleave further downstream caspases, such as Caspase-3, which in turn induces cell apoptosis [41,42,43,44,45][41][42][43][44][45].
Altogether, to make use of these mechanisms such as bacteria-induced apoptosis and metastasis suppression and to establish efficient therapy methods within using bacteria, it is important to meet several framework conditions such as maximum cytotoxicity against cancer cells with minimum cytotoxicity towards intact cell tissue and the ability to selectively attack carcinomas [20,40][20][40].
