Cancer, ranking second among the most commonly encountered diseases worldwide, is exhibiting an increasing incidence over time. Among cancer types, lung cancer, breast cancer, and prostate cancer hold the top three positions. Following these, digestive system cancers are the most frequently observed. The rising cancer-related mortality rates and potential difficulties during treatment exacerbate the fears and concerns of cancer patients. Throughout history, cancer has been attempted to be explained through theories such as lymphatic, humoral, blastoma, trauma, chronic irritation, and parasitic hypotheses. In contemporary times, a wealth of information exists concerning the roles of viruses and bacteria in cancer development. Among bacteria, the sole member acknowledged as a human carcinogen by the International Agency for Research on Cancer (IARC) is Helicobacter pylori. While there is no conclusive evidence regarding Streptococcus bovis's capacity to induce cancer, substantial suspicions surround this matter. This review delves into the relationship between the Streptococcus bovis group of bacteria, which is associated with cancer but not listed by the IARC, and colorectal cancer.

Keywords: streptococcus bovis, colorectal cancer, carcinogens

Throughout the history of medicine, the disease most extensively researched has been cancer. References to cancer and its fatal consequences are found in Babylonian cuneiform tablets, ancient Indian manuscripts, and Egyptian papyri, including the Ebers Papyrus (15th century BC).¹ Today, it stands as a significant issue for all countries worldwide. The projection by the International Agency for Research on Cancer (IARC), a branch of the World Health Organization, for the year 2030 is that cancer will be the leading cause of death.² Among the most commonly encountered cancer types globally, lung cancer, breast cancer, and prostate cancer hold the top three positions. Following these, digestive system cancers are the most prevalent. The increasing cancer-related mortality rates and potential difficulties during treatment amplify the fears and concerns of cancer patients.³ Between the years 1628 and 1694, the first scientific study on cancer was conducted by Marcello Malpighi. In the past, cancer was explained through theories such as humoral, lymphatic, blastoma, chronic irritation, trauma, and parasitic hypotheses.⁴ In 1903, Borrel proposed the idea that cancer could have a viral origin. In 1909, Ellerman and Bank demonstrated that leukemia is contagious among chickens, and in 1956, Dr. Stanley indicated that cancer viruses are present in every individual, and some factors trigger their activation. In 1974, Dr. Mak and Dr. Hawatson from the Ontario Cancer Institute in Canada discovered a virus that causes leukemia in humans.⁵

In recent years, studies have identified associations with viruses, protozoa, helminths, and certain bacteria in various cancer types. Up to this point, particularly in digestive system cancers, certain bacteria (such as Helicobacter bilis, Helicobacter hepaticus, Campylobacter jejuni, Clostridium spp., Bacteroides sp., Salmonella typhi), along with Streptococcus spp. bacteria, have been observed to actively contribute to colorectal cancer (CRC).^5–8

Characteristic features of cancer cells include continuous division without dependence on any factor, resistance to growth-inhibitory signals, lack of response to apoptosis, maintenance of telomere sequences allowing unlimited replication, and the ability to migrate to other regions and generate disease.⁹ Globally, lung and prostate cancers alternately hold the first two places in the deadly ranking. CRC stands as the third most commonly occurring cancer type. Approximately 600,000 individuals worldwide die from colon cancer annually, accounting for around 8% of total cancer deaths worldwide. CRC primarily affects elderly adults; less than 20% of CRCs are found in individuals under 50 years old. However, there is a rapid increase in CRC among the young population, raising questions about lifestyle risk factors and even infectious etiology.¹⁰ The American Cancer Society found a yearly increase in CRC incidence of 2.9% in women and 3.5% in men worldwide from 1992 to 2005. In contrast, there is a 20% decrease in CRC incidence in populations over 50 years old. Overall, an individual's lifetime risk of CRC is approximately 5%.¹¹

CRC includes adenocarcinomas, adenosquamous carcinomas, spindle cell carcinomas, squamous cell carcinomas, mucinous carcinomas, signet ring cell carcinomas, and undifferentiated carcinomas, each having distinct clinical characteristics and requiring slightly different treatment approaches.¹² CRC formation generally evolves from a pre-existing polyp, progressing through stages of adenoma-dysplasia-carcinoma (Figure 1) and attains a lethal size within a span of 5 to 10 years.¹³ This timeline underscores CRC as one of the most preventable cancers through early detection. Particularly, the removal of high-risk polyps before malignant transformation significantly diminishes the risk of cancer.^12,14

Figure 1 The CRC formation.¹⁵

Streptococci

More than 100 species have been identified within the Streptococcus genus to date. Especially with the advancement of next-generation sequencing technologies, this number is likely to increase further. In the past 5 years alone, over 10 new species have been discovered, primarily from the oral cavity and gastrointestinal system of mammals. Streptococci have the potential to cause invasive infections, many of which hold significant public health importance. They can be found as part of the normal flora in the body and can also exist as saprophytes in food items like milk and dairy products.¹⁶

Streptococci constitute a diverse group of microorganisms. They are generally characterized as gram-positive cocci, often appearing in chains or pairs. Unlike staphylococci, streptococci yield negative results in catalase reactions. Many of these microorganisms are facultative anaerobes, meaning they can thrive in both oxygen-rich and oxygen-poor environments. The medically significant streptococci are typically non-motile and lack spores, while some species are enveloped by structures such as capsules composed of polysaccharides or hyaluronic acid. These attributes make them amenable to cultivation in nutrient-enriched media, such as those containing blood or serum. In solid culture media, most of these microorganisms form disk-like colonies with diameters of 1-2 mm.¹⁷

Streptococcus species

Group A Streptococcus; Streptococcus pyogenes

Streptococcus bacteria are among the most common microorganisms causing diseases in humans. When grown on blood agar, they typically form small, grayish colonies with a wide zone of complete hemolysis (beta hemolysis) surrounding them. Among the cellular components of these bacteria, commonly encountered ones include lipoteichoic acid, M protein, capsular polysaccharide, streptokinase, streptolysin, nucleases, hyaluronidase, and erythrogenic toxins. Additionally, streptococci can produce various enzymes, including proteinases, phosphatases, esterases, amylases, N-acetyl glucosamine amidase, neuraminidase, lipoproteinases, ribonucleases, diphosphopyridine nucleotidase, and esterases.¹⁸

Infections caused by Group A Streptococcus can lead to various diseases such as erysipelas, sepsis, endocarditis, puerperal sepsis, toxic shock-like syndrome, skin and subcutaneous tissue infections, streptococcal pharyngitis, scarlet fever, acute rheumatic fever, and acute glomerulonephritis.¹⁹

Group B Streptococcus; Streptococcus agalactiae

B group streptococci, known as Streptococcus agalactiae, generally exhibit characteristics typical of the Streptococcus family. When cultured on blood agar, they form larger, purplish colonies compared to A group streptococci and often have a narrow hemolysis zone around them. However, 5% to 15% of them may not exhibit hemolysis. B group streptococci are commonly found in the genital and intestinal flora of humans, particularly in pregnant individuals, nursery personnel, and newborns, without causing disease.²⁰

Infections caused by these bacteria can include sepsis, pneumonia, osteomyelitis, arthritis, and meningitis in newborns. In adults, they can lead to conditions such as endometritis, endocarditis, pyelonephritis, pneumonia, cellulitis, septic arthritis, and meningitis. B group streptococci present in the vaginal flora of women can also be found in 50% of their partners' urethra, potentially causing urethritis.²¹

Group C Streptococci

Group C Streptococci consist of species like S. equisimilis, S. zooepidemicus, beta-hemolytic S. equi, and S. dysgalactiae, which can also be alpha-hemolytic or non-hemolytic. These bacteria can be responsible for diseases such as pharyngitis, tonsillitis, sepsis, pneumonia, meningitis, osteomyelitis, arthritis, and endocarditis.²²

Group D Streptococci

Their microscopic appearance can be in pairs or short chains of diplococci. Enterococcus faecalis, Enterococcus faecium, and Streptococcus durans are microorganisms that are resistant to penicillin and exhibit alpha, beta, or gamma hemolysis characteristics. Streptococcus bovis and Streptococcus equinus, on the other hand, are non-enterococcal Group D streptococci.²³

Group D streptococci and enterococci are often part of the normal flora in the intestines, mouths, and sometimes the skin of both humans and some animals. Under suitable conditions, they can cause various diseases in humans, including endocarditis, urinary tract infections, abscesses, and cholecystitis.²⁴

Viridans Streptococci

Viridans group streptococci make up 30% to 60% of the normal oral flora in humans. These bacteria can be found on the surfaces of teeth, in the spaces between gums and teeth, in root canals, on the palate, tongue, and the mucous membranes of the pharynx. To cause infections, they need to leave their natural habitat and encounter reduced host resistance. They exhibit alpha hemolysis when grown on blood agar.²⁵

Viridans streptococci can be isolated as the causative agents of dental root infections, subacute bacterial endocarditis, chronic lung infections, genital and urinary infections, cholangitis, peritonitis, and various abscesses.^18,25

Other streptococcus species

Aerococcus

These bacteria have a size of 1.0-2.0 micrometers and form tetrads. They are gram-positive and microaerophilic, being catalase-negative. When grown on blood agar, they exhibit green hemolysis. Aerococcus is generally considered a saprophytic bacterium and has been isolated from certain cases of endocarditis and hospital environments.¹⁸

Gemella

Gemella bacteria, on the other hand, appear as diplococci or single cocci with flat, opposing faces. They are gram-positive and form colonies on blood agar that resemble small beta-hemolytic streptococcal colonies. This genus includes only one species, Gemella haemolysans.¹⁸

Peptococcus

Peptococcus bacteria are gram-positive cocci that appear singly, in pairs, tetrads, or clusters with a size ranging from 0.3 to 1.3 micrometers. Their colonies on blood agar are small (0.5 mm in diameter), round, shiny, and non-hemolytic, with a black color. Peptococcus niger can be part of the normal flora in the vaginal area and the umbilical region.¹⁸

Peptostreptococcus

Peptostreptococcus bacteria, forming irregular clusters or chains of cocci, are gram-positive anaerobic cocci. Isolating Peptococcus and Peptostreptococcus species can be challenging. Particularly, the presence of gram-positive cocci in direct stained preparations of clinical specimens without growth in aerobic cultures, but with suspected gram-positive cocci in anaerobic cultures, indicates the presence of these bacteria.²⁶

Peptostreptococcus species can be isolated from various sources, including the female genital tract in both normal and pathological conditions, blood in cases of puerperal sepsis, the normal respiratory and intestinal flora of humans and some animals, some pyogenic infections, septic war wounds, and appendicitis.²⁷

Classification of species within the streptococcus genus

Species within the Streptococcus genus are classified based on various factors. These factors encompass serological characteristics of the cell wall, the presence of capsular antigens, colony morphology, types of hemolysis exhibited on blood agar, biochemical reactions, and sensitivity to physical/chemical agents.²⁸

Streptococcus bovis

These bacteria, referred to as S. bovis, are categorized as Streptococcus gallolyticus (formerly S. bovis biotype I), Streptococcus infantarius (S. bovis biotype II.1), and Streptococcus pasteurianus (S. bovis biotype II.2). These bacteria typically form small non-hemolytic or alpha-hemolytic colonies, and they cannot grow in a 6.5% salt solution. They yield negative results in the catalase test, test positively for leucine aminopeptidase, and test negatively for PYR (pyrrolidonyl arylamidase). Gram-positive cocci in pairs or short chains define their morphology.²⁹

These species can be found as normal components of the intestinal flora in about 2-12% of healthy adults. However, they are also prevalent in individuals with gastrointestinal cancer. S. bovis group bacteria express the Lancefield Group D antigen and exhibit phenotypic characteristics reminiscent of enterococci.³⁰ The exact pathogenesis mechanism of S. bovis is not fully understood, and thus, the virulence factors associated with these infections are not completely elucidated. The following are some factors that contribute to the survival and growth of this organism within the host:^31–33

1. Surface proteins: Streptococcus bovis possesses a series of genes encoding microbial surface components recognizing adhesive matrix molecules (MSCRAMM) that can recognize adhesive proteins and other components of the extracellular matrix of host cells. These molecules remain in the organism's cell wall and are specific to certain cells within the host. The genomic sequences of bovis support the presence of three pilus gene clusters known as pil1, pil2, and pil3. Pil1 has been identified as the initial virulence factor and is responsible for biofilm formation even without collagen binding ability. It plays a crucial role in the initial attachment and colonization stages of infective endocarditis. Additionally, the colonization of the intestinal tract by S. bovis has been found to depend on the Pil3 pilus, which aids in bacterial attachment by binding to colonic mucus and fibrinogen in humans.
2. Biofilm formation: Specific bovis strains can create biofilms that can lead to nosocomial (hospital-acquired) infections around medical devices such as catheters. The formation of biofilms serves as a barrier not only against antimicrobial agents but also against immune cells, offering protection to the bacteria. This biofilm formation process is supported by the presence of fibrinogen-binding adhesins and other enzymes.
3. Soluble cell wall antigens: In cases of colorectal cancer caused by S. bovis, soluble cell wall antigens have been identified as playing a significant role in triggering inflammation and carcinogenic processes. These proteins or antigens induce the activity of interleukin-8 (IL-8) in different cell types within the body. IL-8 is known to induce the overexpression of cyclooxygenase-2 (Cox-2), leading to increased prostaglandin levels in Caro-2 cells. This, in turn, results in elevated production of oxygen radicals and nitric oxide in the intestinal mucosa cells, causing mutagenesis that further supports the induction of cancer.

Many Streptococcus species do not thrive well in traditional growth media like Nutrient Agar, necessitating the use of specialized media containing specific carbohydrates and nutrients. Blood agar and Chocolate agar are commonly used for diagnosing S. bovis, with observation of hemolysis patterns being essential. For more selective isolation, specialized media like Brain Heart Infusion Agar and Trypticase Soy Agar/Broth with defibrinated sheep blood can be utilized (Figure 2).³⁴

Figure 2 Microscopic images of Streptococcus bovis on blood agar.³⁵

Pathogenesis of Streptococcus bovis

While Streptococcus bovis is considered a commensal in the gastrointestinal system of animals, it can also lead to various forms of infection. The complete mechanism of infection and the pathogenesis of the disease are not fully understood. However, it is believed that biofilm formation plays a critical role in the organism's growth and survival. Different virulence factors expressed by this organism assist in the pathogenesis process.^36,37

1. Colonization

1. The organism can enter the host's body through various routes, such as oral ingestion of different food sources.
2. Subsequently, bacteria reach the gastrointestinal region and adhere to the epithelial cells of the mucosal layer.
3. Attachment is initiated through "Microbial Surface Components Recognizing Adhesive Matrix Molecules" (MSCRAMM) and other adhesive proteins.
4. The initial attachment process is followed by the binding of pil1 protein, which can attach to collagen and further support colonization.
5. These steps of attachment and colonization are vital for the organism's ability to reproduce, multiply, and establish itself within the body.

2. Invasion

1. Following colonization, bacteria begin to penetrate deeper tissues and can cause infections in various parts of the body by entering the bloodstream.
2. Mucosal damage allows bacteria to enter the bloodstream and cause infective endocarditis.
3. Bacteria can bind to factors like thrombin, thrombocytes, and fibrin, inducing blood clotting and contributing to the organism's protection.
4. Proteins like Pil1 and Pil3 interact with intrinsic clotting pathways, influencing significant events during endocarditis.
5. Soluble cell wall proteins produced by the organism can enhance inflammation and trigger cancer processes.
6. These chemical reactions can induce mutagenesis in mucosal cells, promoting the development of cancer.

Clinical symptoms of streptococcus bovis

Previously, S. bovis was commonly considered a low-grade pathogen associated with bacteremia and endocarditis. In addition to infective endocarditis, the possibility of S. bovis infections has been suggested in various areas such as osteomyelitis, discitis, and neck abscesses outside the colon. Depending on the geographical location of patients, other types of infections such as colorectal adenoma, cholecystitis, cholangitis, and biliary tract diseases have also been linked to S. bovis.^38,39

1. Infective Endocarditis

1. The organism can induce blood clotting by binding to fibrinogen-binding proteins and collagen, leading to infective endocarditis.
2. Patients may experience symptoms like chills, fever, and chest pain.
3. Infective endocarditis has been closely associated with both bacteremia and colon cancer.

2. Malignancies

1. S. bovis bacteremia has been associated with malignancy in approximately 29% of patients with tumor lesions in areas such as the colon, gallbladder, lungs, or others.
2. Chronic inflammation and the production of carcinogenic metabolites can lead to lesions in the colorectal region, providing a foundation for the development of malignancies.

S. bovis and colorectal cancer

S. bovis is a largely commensal species found in the intestines of animals, and it serves as a benign type that helps prevent the colonization of different pathogenic microorganisms. However, in individuals with suppressed immunity, it possesses various structures and proteins that support the colonization and invasion of host tissue surfaces. These structures not only aid the organism in entering the body and initiating invasion but also protect the organism from the host immune system.⁴⁰

The S. bovis group bacteria have long been associated with colorectal cancer (Table 1). Meta-analyses conducted have revealed that patients infected with S. bovis biotype I have a significantly higher risk of developing colorectal cancer compared to those infected with biotype II. This analysis demonstrates that S. bovis is not just a bacterium, but it plays a role in the formation and progression of CRC and certain diseases. However, research has not yet determined whether S. bovis is a causative agent of colorectal cancer or if it aids in the growth and proliferation of pre-existing cancer within the lumen of the colon. Nonetheless, there is a clear established link between this group and colon adenomas/carcinomas based on studies conducted to date.^41,42

Streptococcus bovis is a part of the normal intestinal flora in humans and animals, but it is also responsible for infectious diseases (10-15% of all bacterial endocarditis cases). Various cases of bacteremia and metastatic abscesses involving the spleen, liver, soft tissues, bone, meninges, and endocardium have been reported to be associated with S. bovis, particularly related to colonic diseases, digestive system disorders, and specifically colonic neoplasms or chronic liver diseases.¹¹⁰

Endocarditis and/or bacteremia caused by Streptococcus bovis serve as early indicators of possible colorectal cancer presence. While further studies are needed to determine the exact pathophysiology, clinicians should be aware of this association. Rigorous investigation for colon cancer is advised in all patients presenting with S. bovis endocarditis/bacteremia; such patients may also present with liver disease or, rarely, extracolonic malignancies.¹¹¹

In conclusion, there is strong epidemiological evidence that S. bovis can contribute to colorectal cancer. Moreover, its frequent detection in the majority of CRC cases, its greater and/or higher concentration in malignant tissues compared to corresponding healthy tissues, its localization in tissue at every stage of cancer development, and its support of cancer progression indicate that it should be included in the list of infectious agents by the IARC.¹¹²

Furthermore, cases of infective endocarditis related to the bovis group have shown an increase in recent years.¹¹³ Considering this information, any patient with bovis group bacteremia should undergo echocardiography and colonoscopy, and biliary tract imaging should also be considered. In light of the above data, we believe that clinical trials should be included to explore effective antibiotics against bovis group bacteria in patients with CRC, before resorting to heavy treatments like chemotherapy.

None.

The authors declare that there is no conflict of interest.

1. Feinberg AP, Tycko B. The history of cancer epigenetics. Nature Reviews Cancer. 2004;4:143–153.
2. World Health Organization. 2007:27–30.
3. Pal D, Nayak AK. Nanotechnology for targeted delivery in cancer therapeutics. International Journal of Pharmaceutical Sciences Review and Research. 2010;1(1):1–5.
4. Atici E. Cancer and leukemia in the history of medicine. Türk Onkoloji Dergisi. 2007;22(4):197–204.
5. Sudhakar A. History of cancer, ancient and modern treatment methods. J Cancer Sci Ther. 2009;1(2):1–4.
6. Fox JG, Dewhirst FE, Shen Z, et al. Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. Gastroenterology. 1998;114(4):755–763.
7. Lecuit M, Abachin E, Martin A, et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med. 2004;350(3):239–248.
8. Mizutani T, Mitsuoka T. Effect of intestinal bacteria on incidence of liver tumors in gnotobiotic C3H/He male mice. J Natl Cancer Inst. 1979;63(6):1365–1370.
9. Sporn MB. The war on cancer. Lancet; London, England; 1996;347(9012):1377–1381.
10. O'Connell JB, Maggard MA, Livingston EH, et al. Colorectal cancer in the young. The American Journal of Surgery. 2004;187(3);343–348.
11. Artemev A, Naik S, Pougno A, et al. The association of microbiome dysbiosis with colorectal cancer. Cureus. 2022;14(2):22156.
12. Lucas C, Barnich N, Nguyen HT. Microbiota, inflammation and colorectal cancer. Int J Mol Sci. 2017;18:1310.
13. Deen KI, Silva H, Deen R, et al. Colorectal cancer in the young, many questions, few answers. World J Gastrointest Oncol. 2016;8:481–488.
14. Grady WM, Markowitz SD. The molecular pathogenesis of colorectal cancer and its potential application to colorectal cancer screening. Dig Dis Sci. 2015;60:762–772.
15. Colorectal cancer.
16. Patterson MJ. Streptococcus. Baron S, Editor. In Medical Microbiology. 4th ed, Galveston (TX): University of Texas; 1996.
17. Lean WL, Arnup S, Danchin M, et al. Rapid diagnostic tests for group a streptococcal pharyngitis: a meta-analysis. Pediatrics. 2014;134:771–781.
18. Berkiten R. Gram positive cocci: Laboratory diagnosis, epidemiology, prevention. Medical Microbiology-2. Ankara: Nobel Medical Bookstores; 2005:1–28.
19. Mutlu G, Ömer T, Cengiz T, et al. Streptococcus. Basic and clinical microbiology. Ankara: Gunes Bookstore; 1999;355–364.
20. Ardıç N. Group Streptococci (Streptococcus agalactiae). Klimik Dergisi; 2003;16(3):101–105.
21. Topley WW, Wilson GS. Topley and Wilson’s microbiology and microbial infections. 9th ed. Oxford University Press; New York: 1998;423–460.
22. Lehman DC, Mahon CR, Suvarna K. Streptococcus, enterococcus and other catalase-negative Gram-positive cocci. Textbook of Diagnostic Microbiology-3rd ed. Philadelphia: Elsevier; 2007;382–395.
23. Washington WJ, Allen S, Janda W. Isolation and identification of Streptococci and ‘Streptococcus-Like’ bacteria. Koneman’s Color Atlas and Textbook of Diagnostic Microbiology. Philadelphia: Lippincott Williams & Wilkins: 2006;701–745.
24. Ruoff KL, Bisno AL. “Classification of Streptococci”. Principles and practice of infectious diseases, 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2005:2591–2610.
25. Bilgehan H. Clinical microbiological diagnosis. 3rd Ed. Baris Publications; Izmir: 2002;495–521.
26. Brook I. Clinical review: bacteremia caused by anaerobic bacteria in children. Crit Care. 2002;6:205–211.
27. Töreci K, Berkiten R. Non-pneumococcal streptococcal and enterococcal infections: Laboratory diagnosis, epidemiology, prevention. Medical Microbiology-3. Ankara: Nobel Medical Bookstores; 2008;49–70.
28. O’Brien KL, Wolfson LJ, Watt JP, Henkle et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374(9693):893–902.
29. Parks T, Barrett L, Jones N. Invasive streptococcal disease: a review for clinicians. Br Med Bull. 2015;115(1):77–89
30. Isenring J, Kohler J, Nakata M, et al. Streptococcus gallolyticus subsp. gallolyticus endocarditis isolate interferes with coagulation and activates the contact system. Virulence. 2018;9(1):248–261.
31. Herrera P, Kwon YM, Ricke SC. Ecology and pathogenicity of gastrointestinal Streptococcus bovis. Anaerobe. 2009;15:44–54.
32. Dekker JP, Lau AF. An update on the Streptococcus bovis group: classification, identification, and disease associations. J Clin Microbiol. 2016;54:1694–1699.
33. Jans C, de Wouters T, Bonfoh B, et al. Hylogenetic, epidemiological and functional analyses of the Streptococcus bovis/Streptococcus equinus complex through an overarching MLST scheme. BMC Microbiol. 2016;16:117.
34. Long AT, Kenne E, Jung R. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost. 2016;14:427–437.
35. Toit MD, Huch M, Cho GS, et al. The genus Streptococcus. Lactic Acid Bacteria. John Wiley & Sons, Ltd; 2014;457–505.
36. Abdulamir AS, Hafidh RR, Bakar FA. The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res. 2011;30:11.
37. Tjalsma H, Boleij A. Subtyping of Streptococcus bovis group bacteria is needed to fully understand the clinical value of Streptococcus gallolyticus (S. bovis biotype I) infection as early sign of colonic malignancy. Int J Clin Pract. 2012;66:326–326.
38. Lin IH, Liu TT, Teng YT, et al. Sequencing and comparative genome analysis of two pathogenic Streptococcus gallolyticus subspecies: genome plasticity, adaptation and virulence. PLoS ONE. 2011;6:20519.
39. Sillanpaa J, Nallapareddy SR, Qin X, et al. A collagenbinding adhesin, Acb, and ten other putative MSCRAMM and pilus family proteins of Streptococcus gallolyticus subsp. gallolyticus (Streptococcus bovis group, biotype I). J Bacteriol. 2009;191:6643–6653.
40. Hensler ME. Streptococcus gallolyticus, infective endocarditis, and colon carcinoma: new light on an intriguing coincidence. J Infect Dis. 2011;203:1040–1042.
41. Tsai CE, Chiu CT, Rayner CK, Wu et al. Associated factors in Streptococcus bovis bacteremia and colorectal cancer. The Kaohsiung Journal of Medical Sciences. 2016;32(14):196–200.
42. Galdy S, Nastasi G. Streptococcus bovis endocarditis and colon cancer: myth or reality? A case report and literature review. BMJ Case Reports. 2012.
43. Klein RS, Recco RA, Catalano MT, et al. Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med. 1977;297(15):800–802.
44. Tjalsma H, Schöller-Guinard M, Lasonder E, et al. Profiling the humoral immune response in colon cancer patients: diagnostic antigens from Streptococcus bovis. Int J Cancer. 2006;119(9):2127–2135.
45. Abdulamir AS, Hafidh RR, Mahdi LK, et al. Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma. BMC Cancer. 2009;9:403.
46. Boleij A, Roelofs R, Schaeps RM, et al. Increased exposure to bacterial antigen RpL7/L12 in early stage colorectal cancer patients. Cancer. 2010;116(17):4014–4022.
47. Ellmerich S, Schöller M, Duranton B, et al. Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000;21( 4):753–756.
48. Biarc J, Nguyen IS, Pini A, et al. Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S. bovis). Carcinogenesis. 2004;25(8):1477–1484.
49. Murray HW, Roberts RB. Streptococcus bovis bacteremia and underlying gastrointestinal disease. Arch Intern Med. 1978;138(7):1097–1099.
50. Klein RS, Catalano MT, Edberg SC, et al. Streptococcus bovis septicemia and carcinoma of the colon. Ann Intern Med. 1979;91( 4):560–562.
51. Beeching NJ, Christmas TI, Ellis-Pegler RB, et al. Streptococcus bovis bacteraemia requires rigorous exclusion of colonic neoplasia and endocarditis. Q J Med. 1985;56(220):439–450.
52. Leport C, Bure A, Leport J, et al. Incidence of colonic lesions in Streptococcus bovis and enterococcal endocarditis. Lancet. 1987;1(8535):748.
53. Pigrau C, Lorente A, Pahissa A, et al. Streptococcus bovis bacteremia and digestive system neoplasms. Scand J Infect Dis. 1988;20(4):459–460.
54. Hoppes WL, Lerner PI. Nonenterococcal Group-D Streptococcal Endocarditis Caused by Streptococcus bovis. Annals of Internal Medicine. 1974;81:588–593.
55. Wilson WR, Thompson RL, Wilkowske CJ, et al. Short-term therapy for Streptococcal infective endocarditis. JAMA. 1981;245:360–363.
56. Friedrich IA, Wormser GP, Gottfried EB. The association of remote Streptococcus bovis bacteremia with colonic neoplasia. Am J Gastroenterol. 1982;77(2):82–84.
57. Zarkin BA, Lillemoe KD, Cameron JL, et al. The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Ann Surg. 1990;211(6):786–791.
58. Hoen B, Briançon S, Delahaye F, et al. Tumors of the colon increase the risk of developing Streptococcus bovis endocarditis: case-control study. Clin Infect Dis. 1994;19(2):361–362.
59. Ballet M, Gevigney G, Garé JP, et al. Infective endocarditis due to Streptococcus bovis. A report of 53 cases. Eur Heart J. 1995;16(12):1975–1980.
60. Duval X, Papastamopoulos V, Longuet P, et al. Definite Streptococcus bovis endocarditis: characteristics in 20 patients. Clin Microbiol Infect. 2001;7(1):3–10.
61. Gonzalez Quintela A, Martínez Rey C, Castroagudín JF, et al. Prevalence of liver disease in patients with Streptococcus bovis bacteraemia. J Infect. 2001;42(2):116–119.
62. Pergola V, Di Salvo G, Habib G, et al. Comparison of clinical and echocardiographic characteristics of Streptococcus bovis endocarditis with that caused by other pathogens. Am J Cardiol. 2001;88(8):871–875.
63. Herrero IA, Rouse MS, Piper KE, et al. Reevaluation of Streptococcus bovis endocarditis cases from 1975 to 1985 by 16S ribosomal DNA sequence analysis. J Clin Microbiol. 2002;40(10):3848–3850.
64. González-Juanatey C, González-Gay MA, Llorca J, et al. Infective endocarditis due to Streptococcus bovis in a series of nonaddict patients: clinical and morphological characteristics of 20 cases and review of the literature. Can J Cardiol. 2003;19(10):1139–1145.
65. Lee RA, Woo PC, To AP, et al. Geographical difference of disease association in Streptococcus bovis bacteraemia. J Med Microbiol. 2003;52(10):903–908.
66. Tripodi MF, Adinolfi LE, Ragone E, et al. Streptococcus bovis endocarditis and its association with chronic liver disease: an underestimated risk factor. Clin Infect Dis. 2004;38(10):1394–1400.
67. Gold JS, Bayar S, Salem RR. Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Arch Surg. 2004;139(7):760–765.
68. Jean SS, Teng LJ, Hsueh PR, et al. Bacteremic Streptococcus bovis infections at a university hospital, 1992–2001. J Formos Med Assoc. 2004;103(2):118–123.
69. Alazmi W, Bustamante M, O’Loughlin C, et al. The association of Streptococcus bovis bacteremia and gastrointestinal diseases: a retrospective analysis. Dig Dis Sci. 2006;51(4):732–736.
70. Vaska VL, Faoagali JL. Streptococcus bovis bacteraemia: identification within organism complex and association with endocarditis and colonic malignancy. Pathology. 2009;41(2):183–186.
71. Fernández-Ruiz M, Villar-Silva J, Llenas-García J, et al. Streptococcus bovis bacteraemia revisited: clinical and microbiological correlates in a contemporary series of 59 patients. J Infect. 2010;6(4):307–313.
72. Weitberg AB, Annese C, Ginsberg MB. Streptococcus bovis meningitis and carcinoma of the colon. Johns Hopkins Med J. 1981;148(6):260–261.
73. Robbins N, Klein RS. Carcinoma of the colon 2 years after endocarditis due to Streptococcus bovis. Am J Gastroenterol. 1983;78(3):162–163.
74. Belinkie SA, Narayanan NC, Russell JC, et al. Splenic abscess associated with Streptococcus bovis septicemia and neoplastic lesions of the colon. Dis Colon Rectum. 1983;26(12):823–824.
75. Silver SC. Streptococcus bovis endocarditis and its association with colonic carcinoma. Dis Colon Rectum. 1984;27(9):613–614.
76. Trajber I, Solomon A, Michowitz M, et al. Streptococcus bovis subacute bacterial endocarditis as a presenting symptom of occult double carcinoma of the colon. J Surg Oncol. 1984;27(3):186–188.
77. Friedman E, Elian D, Eisenstein Z. Streptococcus bovis bacteremia and underlying gastrointestinal neoplasms. Med Pediatr Oncol. 1986;14(6):313–315.
78. Tabibian N, Clarridge JE. Streptococcus bovis septicemia and large bowel neoplasia. Am Fam Physician. 1989;39(4):227–229.
79. McMahon AJ, Auld CD, Dale BA, et al. Streptococcus bovis septicaemia associated with uncomplicated colonic carcinoma. Br J Surg. 1991;78(7):883–885.
80. Almeida J, Bau J, Baptista I, et al. Adenocarcinoma of the colon disclosed by endocarditis caused by Streptococcus bovis. Acta Med Port. 1992;5(6):335–337.
81. Ma HM, Shyu KG, Hwang JJ, et al. Streptococcus bovis endocarditis associated with colonic adenocarcinoma: report of a case. J Formos Med Assoc. 1992;91(8):814–817.
82. Copeland LG, Malster MG. Suspicious mind: the association between Streptococcus bovis endocarditis and carcinoma of the colon. Postgrad Med J. 1993;69(809):241.
83. Goumas PD, Naxakis SS, Rentzis GA, et al. Lateral neck abscess caused by Streptococcus bovis in a patient with undiagnosed colon cancer. J Laryngol Otol. 1997;111(7):666–668.
84. Waisberg J, Matheus CO. Pimenta, J. Infectious endocarditis from Streptococcus bovis associated with colonic carcinoma: case report and literature review. Arq Gastroenterol. 2002;39(3):177–180.
85. Vince KG, Kantor SR, Descalzi J. Late infection of a total knee arthroplasty with Streptococcus bovis in association with carcinoma of the large intestine. J Arthroplasty. 2003;18(6):813–815.
86. Weng SW, Liu JW, Chen WJ, et al. Recurrent Klebsiella pneumoniae liver abscess in a diabetic patient followed by Streptococcus bovis endocarditis occult colon tumor plays an important role. Jpn J Infect Dis. 2005;58(2):70–72.
87. Aizawa K, Kaminishi Y, Kawamata N, et al. Simultaneously performed mitral valve replacement and Hartmann’s operation for infectious endocarditis from Streptococcus bovis and rectal cancer. Jpn J Thorac Cardiovasc Surg. 2006;54(9):413–415.
88. Wentling GK, Metzger PP, Chua HK, et al. Unusual bacterial infections and colorectal carcinoma – Streptococcus bovis and Clostridium septicum : report of three cases. Dis Colon Rectum. 2006;49(8):1223–1227.
89. Kok H, Jureen R, Soon CY, Tey BH. Colon cancer presenting as Streptococcus gallolyticus infective endocarditis. Singapore Med J. 2007;48(2):43–45.
90. Apsingi S, Kulkarni A, Gould KF, et al. Late Streptococcus bovis infection of knee arthroplasty and its association with carcinoma of the colon: a case report. Knee Surg Sports Traumatol Arthrosc. 2007;15(6):761–762.
91. Bleibel W, D’Silva K, Elhorr A. Streptococcus bovis endophthalmitis: a unique presentation of colon cancer. Dig Dis Sci. 2007;52(9):2336–2339.
92. Ferrari A, Botrugno I, Bombelli E. Colonoscopy is mandatory after Streptococcus bovis endocarditis: a lesson still not learned. Case report. World J Surg Oncol. 2008;6:49.
93. Florescu M, Benea DC, Cerin G, et al. Aorto-pulmonary fi stula as a late complication of multiple valve replacement after Streptococcus bovis endocarditis in a patient with occult colon carcinoma. J Clin Ultrasound. 2009;37(6):369–373.
94. Gupta A, Madani R, Mukhtar H. Streptococcus bovis endocarditis, a silent sign for colonic tumour. Colorectal Dis. 2010;12(3):164–171.
95. Barcelos AM, Teixeira MA, Alves LS, et al. Infectious endocarditis due to Streptococcus bovis in a patient with colon carcinoma. Arq Bras Cardiol. 2010;95(3):88–90.
96. Srivastava A, Walter N, Atkinson P. Streptococcus bovis infection of total hip arthroplasty in association with carcinoma of colon. J Surg Orthop Adv. 2010;19(2):125–128.
97. Ng SC, Wong HK, So CK, et al. Streptococcus bovis bacteraemia should be investigated for early detection of colorectal pathology. Hong Kong Med J. 2019;25:414.
98. Agnes A, Biondi A, Belia F, et al. Association between colorectal cancer and Streptococcus gallolyticus subsp. pasteuranus (former S. bovis) endocarditis: clinical relevance and cues for microbiota science. Case report and review of the literatüre. Eur Rev Med Pharmacol Sci. 2021; 25:480–486.
99. Sharara AI, Hamdan TA, Malli A, et al. Association of Streptococcus bovis endocarditis and advanced colorectal neoplasia: A case–control study. Journal of Digestive Diseases. 2013;14:382–387.
100. Abeni C, Rota L, Ogliosi C, et al. Correlation among Streptococcus bovis, endocarditis and septicemia in a patient with advanced colon cancer: a case report. Journal of Medical Case Reports. 2013;7:185.
101. Chime C, Patel H, Kumar K, et al. Colon Cancer with Streptococcus gallolyticus Aortic Valve Endocarditis: A Missing Link? Case Rep Gastrointest Med. 2019;4205603.
102. Alozie A, Köller K, Pose L, et al. Streptococcus bovis infectious endocarditis and occult gastrointestinal neoplasia: experience with 25 consecutive patients treated surgically. Gut Pathog. 2015;7:27.
103. Deng Q, Wang C, Yu K, et al. Streptococcus bovis Contributes to the Development of Colorectal Cancer via Recruiting CD11b+TLR-4+ Cells. Med Sci Monit. 2020;26:e 921886.
104. Eldegla HE, Abdel-Wahhab M, Moemen D. Association between Streptococcus gallolyticus and colorectal cancer in Mansoura University hospitals. Egyptıan Journal of Basıc and Applıed Scıences. 2021;8(1):397–406.
105. Bashir S, Alatery A. Association between Streptococcus bovis and colorectal cancer among Libyan patients. MSediterr J Pharm Pharm Sci. 2021;1(4):50–58.
106. Galdy S, Nastasi G. Streptococcus bovis endocarditis and colon cancer: myth or reality? A case report and literature review. BMJ Case Reports. 2012;2012006961.
107. Riyaaz AAA, Samarasinghe R, Sellahewa K, et al. Native Valve Streptococcus bovis Endocarditis and Refractory Transfusion Dependent Iron Deficiency Anaemia Associated with Concomitant Carcinoma of the Colon: A Case Report and Review of the Literature. Case Rep Infect Dis. 2016(12):1–4.
108. Tab HA, Zidan A, Elfeky HM, et al. Association between Streptococcus gallolyticus and Colorectal Cancer in Egyptian Patients. Egyptian Journal of Medical Microbiology. 2019;28(3):85-93.
109. Little DHW, Onizuka KM, Khan KJ. Referral for Colonoscopy in Patients with Streptococcus bovis Bacteremia and the Association with Colorectal Cancer and Adenomatous Polyps: A Quality Assurance Study. Gastrointest. Disord. 2019;1:385–390.
110. Tripodi MF, Adinolfi LE, Ragone E, et al. Streptococcus bovis Endocarditis and Its Association with Chronic Liver Disease: An Underestimated Risk Factor. Clinical Infectious Diseases. 2004;38(10):1394–1400.
111. Ellmerich S, Schöller M, Duranton B, et al. Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000;21(4):753–756.
112. Dekker JP, Lau AF. An Update on the Streptococcus bovis Group: Classification, Identification, and Disease Associations. Journal of Clinical Microbiology. 2016;54(7):1694–1699.
113. Moellering RC, Watson BK, Kunz LJ. Endocarditis due to group D Streptococci: Comparison of disease caused by Streptococcus bovis with that produced by the enterococci. The American Journal of Medicine. 1974;57(2):239–250.