Cancer is one of the most important leading causes of death all over the world, so it’s important to characterize the causes of this disease and its


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Introduction
Cancer is one of the most important leading causes of death all over the world, so it’s important to characterize the causes of this disease and its pathogenesis in order to find the proper medication.

In modern oncology the damage of the genetic apparatus of the cell is considered to be the main cause of cancer development, and the pathogenesis of cancer is seen as a process of transformation of normal cells into a tumor cells, which have uncontrolled rate of growth that enable them to invade adjacent structures and then destroy the surrounding tissues and organs (1,2). This uncontrolled growth of the cells may interfere with one or more of a person’s vital organs or functions leading to death. Generally, there is three etiological causes of cancer: chemical carcinogenesis (chemical carcinogens), physical carcinogenesis (ionizing radiation, ultraviolet radiation) and biological carcinogenesis (viruses, bacteria, fungi), which is our main concern in this paper. But regardless the cause of the cancer it still has the same pathophysiological mechanism.
Common Pathophysiological Mechanism of Cancer Disease

In general, the submitted pathophysiological mechanism: multiple permanent (prolonged) tissue micro damages in combination with sympathetic/hyper sympathetic dominance provide permanent (prolonged) maintenance of cell proliferation with systemic inhibition of anti-tumor immunity can be called “Cancer reparative trap” (3).

To simplify this pathophysiological mechanism we need to understand the physiological conditions in our body. Generally under physiological conditions, there is a temporary suppression of the (anti-tumor activity of immune system) during any natural reparative process which is always observed when local tissues of the organism are damaged as a result of any chemical, physical or biological impacts. This temporary local suppression of anti-tumor immunity is considered important to ensure successful repair of the damaged tissues (4). To clarify this point, we have to mention that there is a similarity between proliferating tissue cells and tumor cells as they are similar in structure and properties, so if this process wasn’t blocked during tissue repair it will remove the proliferating tissues considering it as a tumor cells that would block the repair process of the damaged tissues (5), and this would explain why local temporary suppression of antitumor immunity is considered as a key factor in the success of the tissue repair process(6,7).

Upon the completion of reparation and reduction of inflammation, the “anti-tumor immunity” will be reactivated and there will be an accumulation of CD8+ cells at the site of injury (type of cytotoxic cells responsible about killing malignant cells), to protect the organism from malignantly transformed cells, which are practically always appear in the area of inflammation (8). Also, the balance of sympathetic and parasympathetic parts of the autonomic nervous system provides for normal physiological flow of the presented processes. This is the natural physiological mechanism of tissue repair but when the body organisms are exposed to a multiple micro-damages caused by the impact of exogenous factors (chemical, physical and biological carcinogens), along with an imbalance in the autonomic nervous system with sympathetic dominance which causes ischemia and tissue hypoxia, then this is considered as a pathophysiological condition. Consequently it will cause constant maintenance of cell proliferation accompanied by systemic inhibition activity of the anti-tumor immunity leading to a chronic inflammation with a permanent formation of cancer cells (8).

In this paper we are going to discuss the relation between biological microorganisms (bacteria, viruses, fungi) and cancer, and the most known mechanisms in which these organisms can cause cancer. Also, the latest known methods of treatment will be discussed in this paper.

Relation between bacteria and cancer
Helicobacter-pylori and Gastric cancer

The association of bacterial infections and tumorigenesis has long remained controversial, as they were not able to detect whether the bacteria is the cause of the cancer, or its accumulation in the tumors is due to the high vascularization and metabolic activity of the cancer cells (9). Until the end of the 20th century, when they found an evidence of bacterial involvement in the inflammation-induced cancer comes from infections with Helicobacter pylori, and by 1994 Helicobacter pylori was recognized as carcinogenic agent (10). Since then, it has been increasingly considered as the strongest known risk factor for gastric adenocarcinoma. On the other hand, it is associated with a reduced risk of developing esophageal adenocarcinoma.
What is Helicobacter pylori?

It is a spiral shaped bacterium that grows in the mucus layer of the stomach, which can tolerate the acidic conditions of the stomach and even reduce it by secreting an enzyme called urease that can convert urea into ammonia, which consequently reduces the acidity of the stomach, making it more hospitable for the bacterium. Also, H-pylori is considered resistant to immune cells, because immune cells are unable to reach stomach lining. In addition H-pylori has developed ways of interfering with local immune responses, making them ineffective in eliminating this bacterium (11).

This bacteria spreads through contaminated food, water and direct mouth-to-mouth contact.
Gastric cancer

It is the second most common cause of cancer related deaths in the world, and it was divided by scientists, into two main classes which is: gastric cardia cancer (cancer of the top inch of the stomach where it meets the esophagus) and non-cardia gastric cancer (cancer in all other areas of the stomach). A lot of epidemiological studies have shown that individuals infected with H-pylori have an increased risk of gastric adenocarcinoma, mainly the non – cardia gastric cancer (12-16). Also, another study-compared subjects who developed non-cardia gastric cancer with cancer free control subjects, found that H-pylori infected individuals had a nearly eightfold increased risk for non-cardia gastric cancer (17). On the other hand, researchers have detected an inverse relationship between H-pylori and gastric cardia cancer, that was proven by a Swedish study showed that the risk of esophageal adenocarcinoma in H-pylori infected individuals was one third that of uninfected individuals (18).
How can H-pylori increase the risk of certain cancers and decrease the risk of others?

It is not known how can H-pylori cause cancer exactly, but the most known hypothesis that is supported by studies suggested that H-pylori can cause certain inflammatory responses, and the long term exposure of the cells in the stomach to these responses may prepare them to become cancerous, there is a study that supported this hypothesis in which they found that, the increased expression of single cytokine (interleukin-1-beta) in the stomach of transgenic mice causes sporadic gastric inflammation and cancer (19). Also, the increased cell turnover from ongoing cellular damage could increase the likelihood that the cells will develop harmful mutations .But what really needs to be more explained is how H-pylori can reduce esophageal adenocarcinoma ? And that was explained by a study stated that H-pylori can reduce the gastric acidity after decades of its colonization in the stomach, consequently this decline would reduce acid reflux into the esophagus which is a major risk factor for adenocarcinoma affecting the upper stomach and esophagus.
Types of Helicobacter-pylori

Certain types of H-pylori carry a gene called cytotoxin associated gene A (cagA), these types use a needle like appendage to inject a toxin produced by this gene into the junctions where the cells of the stomach lining meet. This toxin alters the structure of the stomach cells allowing the bacteria to attach to them more easily. Also, the long exposure to this toxin can cause a chronic inflammation. However, not all strains of H-pylori carry this gene but those that do are classified as (cagA +ve). Those (cagA +ve) H-pylori also has the ability to inactivate the tumor suppressor proteins (20-21).

A Meta-analysis conducted all over the world showed that individuals infected with (cagA +ve) H-pylori had twice risk of developing non cardia gastric cancer than those who were infected with –ve (cagA) H-pylori (22).
The effect of H-pylori treatment on gastric cancer rates

Depending on a randomized clinical trial carried out in china, they found that short-term treatment with antibiotics and PPI to eradicate H-pylori reduced the incidence of gastric cancer by 40% (23).
Chlamydophila pneumoniae and lung cancer

As we have mentioned before scientists through the years tried to understand cancer and connect it with its cause in order to control it. One of the cancers that was studied is the lung cancer since the statistics shows that it is the leading cause of cancer death in the United State, 6 out of every 10 people with lung cancer die within 1 year of finding out.

Chlamydophila pneumoniae is a Gram-negative bacillus and an intracellular parasite that causes respiratory infection in more than 50% of adults. The route of transmission is usually by aerosol and in most cases these infections are mild. The bacterium is, however, an important cause of pneumonia, bronchitis, sinusitis, rhinitis and chronic obstructive pulmonary disease. Respiratory infections from Chlamydophila pneumoniae vary in different countries and populations.

In the study by DL Mager (24). A relationship between Chlamydophila pneumoniae and lung cancer was examined. Chlamydophila (also known as Chlamydia) pneumoniae infection has been implicated in several chronic lung diseases by direct antigen detection. Acute lower respiratory tract infection caused by Chlamydophila pneumoniae seems often to be connected not only with asthma attacks in both children and adults but is also involved in some exacerbations of chronic bronchitis. More importantly it seems to be strongly associated with chronic obstructive lung disease irrespective of exacerbation status. Therefore, persistently elevated Chlamydophila pneumoniae antibody have been observed in lung cancer.

After acute infection the Chlamydophila pneumoniae intracellular lifecycle is characterized by the development of metabolically inert and antibiotic resistant atypical persistent inclusions. These inclusions contain quantities of chlamydial heat shock protein 60, a highly immunogenic protein implicated in the pathogenesis of chronic chlamydial infections. The resulting clinical course is acute symptomatic illness followed by chronic respiratory symptoms. Research also suggests that persistent Chlamydophila pneumoniae inflammation correlates with increased risk of lung cancer.
Statistics:

The study which was done be Kocazeybek et al. (25) included 123 patients how were diagnosed with lung carcinoma, by taking 5 ml blood sample at the minute of diagnosis and another sample 1 month after it. they measured the IgG and igA in both samples an IgG value higher than 512 and IgA value higher than 40 was set as criteria for chronic Chlamydophila pneumonia. We found that 56% of the males were diagnosed with Chlamydophila pneumoniae after being diagnosed with lung cancer and only 36% of the women was seen with Chlamydophila pneumoniae function protein resulting in impairments in cell cycle control, cellular repair and apoptosis.

Streptococcus bovis and colorectal cancer

Colorectal cancer (CRC) is a common malignancy in developed countries and is the 3rd most common cancer in the United States (26)

Streptococcus bovis is a normal inhabitant of the human gastrointestinal tract that can cause bacteremia, endocarditis, and urinary infection (27).

Many kinds of bacteria have been linked to chronic infections of the colon and increased risk of colon cancer including Escherichia coli and several streptococci (28). Recent studies also have showed some kind of association between colon cancer and Streptococcus bovis (29) as 25–80% of patients who presented with a Streptococcic bovis bacteremia had a colorectal tumor. The incidence of S. bovis associated colon cancer has been determined as 18% to 62% (30)

45 cases of streptococcus bovis infection were studied by Golde et al. (31). Patient records were reviewed to identify the presence of colonic neoplasia by using gastrointestinal endoscopy. 39% of adult patients who went through the colonoscopy present colonic neoplasia. invasive cancer was present in 32% of the patients. The authors concluded that Streptococcus bovis exerts its pathological activity in the colonic mucosa only when pre neoplastic lesions are established.

As many studies concluded that the ability of the streptococcus bovis to cause cancer came from its antigen (WEA) that can promote the cancer formation (32).

As we can see in the study done by Biarc et al. (33) that isolated 12 streptococcus bovis cell associated proteins (S300) and WEA and injected them in rates. The purified S300 fraction was able to trigger the rat colonic mucosa to release chemokines (human IL-8 or rat CINC/GRO) and prostaglandin E2 (PgE2). The 12 Streptococcus bovis proteins were highly effective in the promotion of paraneoplastic lesions also the S300 proteins were able to induce a 5-fold increase in PGE2 secretion from Caco-2 cells, as compared with cells stimulated with WEA. The study found that PGE2 release in the rat cells correlated with an over-expression of cyclooxygease-2 (COX-2).

Evidence has shown that over-expression of COX-2 has a major role in mucosal inflammation and is associated with inhibition of apoptosis and enhancement of angiogenesis which favor cancer initiation and development. It was reported by Biarc et al. (34)] that S. bovis proteins also promoted cell proliferation by triggering mitogen-activated protein kinases (MAPKs), which can increase the incidence of cell transformation, the rate of genetic mutations and up-regulate COX-2. The investigators concluded that colonic bacteria such as Streptococcus bovis can contribute to cancer development particularly in chronic infection/inflammation diseases where bacterial components may interfere with cell function (35).
Relation between viruses and cancer
History of associating viruses with cancers

Back in the classical times, it was thought that cancers were due to an infection. The idea was supported by the prevalence of the same cancer amongst married couples and family members.However after extensive investigations in the 19th century, the carcinogenic role of bacteria, fungi and parasites couldn’t be proved. Despite that, certain scientists believed that there were infectious bodies of sub-microscopic size may be linked with cancer [36].It was not until the early 19th century when oncogenic viruses were isolated from birds and later other animals (37). Still, this couldn’t be related to the correlation between viruses and cancers in humans. After the accomplishments of the animal tumor virus field, scientists began the search for human tumor viruses. However, early attempts to isolate transmissible carcinogenic viruses from human tumors were disappointing, raising doubts again about the existence of human cancer viruses.

In 1964 Epstein-Barr virus (EBV) was discovered by electron microscopy (EM) in cells cultured from Burkitt’s lymphoma (BL), and in 1970 hepatitis B virus (HBV) was discovered in human sera positive for hepatitis B surface antigen; together these two discoveries have raised hope again to investigate further in the matter(38,39). In the early 1980s, three major discoveries have led to the ultimate acknowledgement of the casual relationship between viruses and cancer. The first was in 1983 and 1984; human papillomavirus (HPV) 16 and 18 were isolated from human cervical cancer specimens. (40, 41).

Additionally, the results of a large-scale epidemiological study provided a tight link between persistent HBV infection and liver carcinogenesis. Thirdly was the isolation of the human T-cell leukemia virus (HTLV-I) from T-cell lymphoma/leukemia patients. Today, viruses are accepted as causes of human cancers, and it has been estimated that between 15 and 20% of all human cancers may be caused by viruses (42,43).

Human oncogenic viruses share mutual features; one is their ability to infect, but not kill, their host cell. In contrast to many other viruses that cause disease, oncogenic viruses have the tendency to establish long-term persistent infections. Consequently, they have evolved strategies for evading the host immune response, which would otherwise clear the virus during these persistent infections. Despite the viral etiology behind many cancers, it appears that viruses contribute with many other co-factors in carcinogenesis but are not sufficient to cause it on their own. In patients that are tumor virus infected only develop cancer many years after the initial infection with the virus. Other co-factors include host immunity and chronic inflammation, as well as additional host cellular mutations.  Thus, the longstanding interactions between virus and host are key features of the oncogenic viruses (44).


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