Amitabha Ray

Human papillomavirus (HPV) is the most common sexually transmitted infectious agent in the United States as well as globally. This review aims to examine neoplastic diseases associated with HPV with special emphasis on cancers of the uterine cervix and oropharynx. Among the group of high-risk HPVs, i.e., types of HPV that can cause abnormal cellular changes leading to malignancies, HPV genotypes 16 and 18 are commonly found in cervical cancer, whereas HPV-16 is the most detected HPV in oropharyngeal cancer. It is known that the HPV genome comprises three major functional regions: the early region, which encodes proteins such as E6 and E7; the long control region; and the late region, which encodes structural capsid proteins L1 and L2. The E6 and E7 proteins are pivotal to carcinogenesis. E6 promotes degradation of the tumor suppressor p53, while E7 inactivates the retinoblastoma protein, critically disrupting cell cycle regulation and enabling uncontrolled proliferation. These disruptions promote survival of HPV-infected cells–a requirement for the viral life cycle. The viral L1, the major capsid component, is used for classification, PCR detection, antigenic tests, and in prophylactic vaccine preparation. However, it is important to correlate the role of HPV with different risk factors, particularly when considering a wide variation in cervical cancer incidence rates in different nations and geographic regions. Compared to cervical cancer, HPV-positive oropharyngeal cancer risk factors are thought to be associated with sexual behavior primarily. Overall, the local microbial environment of both the cervicovaginal region and the oral cavity may play a significant role in cancer development. For example, an increase in certain bacteria has been documented in the course of disease, such as Fusobacterium in oropharyngeal cancer or Prevotella and Gardnerella in bacterial vaginosis. On the other hand, a depletion of beneficial bacteria in the cervicovaginal environment may contribute to the development of cervical neoplasia. In the case of cervical cancer, all risk factors possibly alter the cervicovaginal microbial flora adversely. The dominance of anaerobic bacteria could bring about pathological changes. In relation to the disease progression, an increasing level of Lactobacillus depletion has been reported. Similarly, in different head and neck cancers, investigators documented differences in bacterial genera between HPV-positive and HPV-negative cases. Furthermore, some investigators suggested that certain bacteria could serve as cancer biomarkers in oral regions. Various bacteria are present throughout the gastrointestinal tract, particularly in the large intestine (colon), where they form the largest populations, and they influence diverse pathophysiological processes both inside and outside the gut. The gut microbiota is a typical example of how alterations in it could be associated with pathological processes, including cancer development. Regarding their impact on other organs, different bidirectional communication networks have been proposed. One pertinent example is the gut–vaginal axis, which connects the microbial communities of these two organs. Currently, a growing number of studies are trying to manipulate this axis and reconstitute the cervicovaginal microbial flora in a favorable manner. Therefore, appropriate modifications of the local microbial environment could prevent pathological processes in an economical way.

Cancer of the uterine cervix (cervical cancer) is a leading cancer among women worldwide, although its incidence has been reducing in many developing nations. In the majority of cervical cancer cases, the presence of high-risk human papillomavirus (HPV) is usually detected. However, a growing body of evidence currently considers that exclusive HPV infection may not be sufficient for cancer development. Apart from certain common risk factors for cervical cancer, like poor nutritional status and smoking, many studies documented an association with other viral infections, such as human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). Similarly, vaginal bacterial populations perhaps play a key role in cervical cancer. It may be worth mentioning that different bacterial species can immensely influence (either protecting or adversely) the biochemical characteristics of the cervicovaginal environment—for example, Lactobacillus crispatus, Gardnerella vaginalis, and Chlamydia trachomatis. As a result, chronic infections with unfavorable microorganisms (other than HPV) may affect the pathological processes of malignancy. On the other hand, the cervix is an estrogen-sensitive organ like the corpus uteri (i.e., the body of the uterus). Estrogen and different estrogen receptors are implicated in the development and promotion of various cancers, including endometrial cancer. A number of reports also suggest a close association between estrogen and HPV in the development of cervical cancer. Furthermore, estrogen is linked with the characteristics of the vaginal microenvironment including bacteria. Therefore, several of the abovementioned factors (some are preventable) could play an important role in the progression of cervical neoplastic lesions.

The gastrointestinal and respiratory systems are closely linked in different ways, including from the embryological, anatomical, cellular, and physiological angles. The highest number (and various types) of microorganisms live in the large intestine/colon, and constitute the normal microbiota in healthy people. Adverse alterations of the microbiota or dysbiosis can lead to chronic inflammation. If this detrimental condition persists, a sequence of pathological events can occur, such as inflammatory bowel disease, dysplasia or premalignant changes, and finally, cancer. One of the most commonly identified bacteria in both inflammatory bowel disease and colon cancer is Escherichia coli. On the other hand, patients with inflammatory bowel disease are at risk of several other diseases—both intestinal (such as malnutrition and intestinal obstruction, besides cancer) and extraintestinal (such as arthritis, bronchiectasis, and cancer risk). Cancers of the lung and colon are the two most common malignancies occurring worldwide (except for female breast cancer). Like the bacterial role in colon cancer, many studies have shown a link between chronic Chlamydia pneumoniae infection and lung cancer. However, in colon cancer, genotoxic colibactin-producing E. coli belonging to the B2 phylogroup may promote tumorigenesis. Furthermore, E. coli is believed to play an important role in the dissemination of cancer cells from the primary colonic site. Currently, seven enteric pathogenic E. coli subtypes have been described. Conversely, three Chlamydiae can cause infections in humans (C. trachomatis may increase the risk of cervical and ovarian cancers). Nonetheless, striking genomic plasticity and genetic modifications allow E. coli to constantly adjust to the surrounding environment. Consequently, E. coli becomes resistant to antibiotics and difficult to manage. To solve this problem, scientists are thinking of utilizing suitable lytic bacteriophages (viruses that infect and kill bacteria). Several bacteriophages of E. coli and Chlamydia species are being evaluated for this purpose.

In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/β-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/β-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.

Infection with the SARS-CoV-2 virus (COVID-19 disease) can cause a wide range of clinical situations – from an asymptomatic state to fatal outcomes. In cases of serious clinical manifestations, the underlying mechanisms involve a number of immune cells and stromal cells as well as their products such as pro-inflammatory interleukin-6 and tumour necrosis factor-alpha that ultimately cause the cytokine storm. The situation of overproduction of pro-inflammatory cytokines is somewhat similar to, though in a mild form, health conditions in obesity and related metabolic disorders like type-2 diabetes, which are also considered important risk factors for severe illness in COVID-19. Interestingly, neutrophils perhaps play a significant role in this pathogenesis. On the other hand, it is thought that COVID-19-related critical illness is associated with pathological hyperactivity of the complement system and coagulopathy. Although the precise molecular interactions between the complement and coagulation systems are not clear, we observe an intimate cross-talk between these two systems in critically ill COVID-19 patients. It is believed that both of these biological systems are connected with the cytokine storm in severe COVID-19 disease and actively participate in this vicious cycle. In order to hinder the pathological progression of COVID-19, a number of anticoagulation agents and complement inhibitors have been used with varying success. Among these drugs, low molecular weight heparin enoxaparin, factor Xa inhibitor apixaban, and complement C5 inhibitor eculizumab have been commonly used in patients with COVID-19. Our overall experience might help us in the future to tackle any such conditions.

About one-fourth of the global population is either overweight or obese, both of which increase the risk of insulin resistance, cardiovascular diseases, and infections. In obesity, both immune cells and adipocytes produce an excess of pro-inflammatory cytokines that may play a significant role in disease progression. In the recent coronavirus disease 2019 (COVID-19) pandemic, important pathological characteristics such as involvement of the renin-angiotensin-aldosterone system, endothelial injury, and pro-inflammatory cytokine release have been shown to be connected with obesity and associated sequelae such as insulin resistance/type 2 diabetes and hypertension. This pathological connection may explain the severity of COVID-19 in patients with metabolic disorders. Many studies have also reported an association between type 2 diabetes and persistent viral infections. Similarly, diabetes favors the growth of various microorganisms including protozoal pathogens as well as opportunistic bacteria and fungi. Furthermore, diabetes is a risk factor for a number of prion-like diseases. There is also an interesting relationship between helminths and type 2 diabetes; helminthiasis may reduce the pro-inflammatory state, but is also associated with type 2 diabetes or even neoplastic processes. Several studies have also documented altered circulating levels of neutrophils, lymphocytes, and monocytes in obesity, which likely modifies vaccine effectiveness. Timely monitoring of inflammatory markers (e.g., C-reactive protein) and energy homeostasis markers (e.g., leptin) could be helpful in preventing many obesity-related diseases.

Obesity has an influence on the risk and prognosis of different types of cancers of the female reproductive tract. In the uterus, a common site for neoplasms is the endometrium, the inner lining tissue. Generally, obesity has been documented to be involved in endometrioid carcinoma of the endometrium. Obesity may influence the cancer risk by various mechanisms such as chronic inflammation, dysregulation of sex hormones and abnormal secretion of hormone-like cytokines or adipokines from adipose tissue. One of the important pro-inflammatory adipokines is leptin, which acts via its transmembrane receptors (Ob-R). In normal conditions, leptin functions in the hypothalamic anorexigenic pathway to maintain the energy homeostasis. Conversely, in obesity, leptin participates in the pro-inflammatory processes. Several clinical studies have suggested that leptin and Ob-R play a role in the pathological processes of endometrial cancer. In different endometrial cancer cell lines, laboratory findings also have demonstrated leptin's link to various neoplastic phenomena such as cellular proliferation, angiogenesis, and oestrogenic activity. Furthermore, endometrial cancer risk could be increased in ovarian pathology like polycystic ovary syndrome, which is commonly associated with obesity. It is noteworthy that leptin participates in both physiological and pathological conditions of the ovary. Leptin has shown pro-tumorigenic effects in both in-vitro and in-vivo studies. Generally, reduced serum leptin levels have been observed in ovarian cancer patients. However, overexpression of leptin and Ob-R in ovarian cancer tissue has indicated aggressive disease. Understanding the role of leptin-related intracellular signalling pathways in tumour development could be helpful in early cancer detection.

Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

Obesity or overweight is a risk factor for several health disorders such as type 2 diabetes, hypertension, and certain cancers. Furthermore, obesity affects almost all body systems including the extracellular matrix (ECM) by generating a pro-inflammatory environment, which are associated with abnormal secretions of several cytokines or hormonal substances, for example, insulin-like growth factors (IGFs), leptin, and sex hormones. These chemical mediators most likely have a great impact on the ECM. Accumulating evidence suggests that both obesity and ECM can influence tumor growth and progression through a number of chemical mediators. Conversely, cells in the connective tissue, namely fibroblasts and macrophages, support and aggravate the inflammatory situation in obesity by releasing several cytokines or growth factors such as vascular endothelial growth factor, epidermal growth factor, and transforming growth factor-beta (TGF-β). A wide range of functions are performed by TGF-β in normal health and pathological conditions including tumorigenesis. Breast cancer in postmenopausal women is a classic example of obesity-related cancer wherein several of these conditions, for example, higher levels of pro-inflammatory cytokines, impairment in the regulation of estrogen and growth factors, and dysregulation of different ECM components may favor the neoplastic process. Aberrant expressions of ECM components such as matrix metalloproteinases or matricellular proteins in both obesity and cancer have been reported by many studies. Nonstructural matricellular proteins, viz., thrombospondins, secreted protein acidic and rich in cysteine (SPARC), and Cyr61-CTGF-Nov (CCN), which function as modulators of cell-ECM interactions, exhibit protean behavior in cancer. Precise understanding of ECM biology can provide potential therapeutic targets to combat obesity-related pathologies.

In general, human pathogen-related small circular deoxyribonucleic acid (DNA) molecules are bacterial plasmids and a group of viral genomes. Plasmids are extra-chromosomal small circular DNAs that are capable of replicating independently of the host, and are present throughout a variety of different microorganisms, most notably bacteria. While plasmids are not essential components of the host, they can impart an assortment of survival enhancing genes such as for fertility, drug resistance, and toxins. Furthermore, plasmids are of particular interest to molecular biology especially in relation to gene-cloning. Among viruses, genomes of anelloviruses, papillomaviruses, and polyomaviruses consist of small circular DNA. The latter two virus families are known for their potential roles in a number of pathogenic processes. Human papillomaviruses (HPV) are now widely recognised to be associated with a greatly increased risk of cervical cancer, especially oncogenic strains 16 and 18. On the other hand, human cells may contain several types of small circular DNA molecules including mitochondrial DNA (mtDNA). The mitochondrial genome consists of 37 genes that encode for proteins of the oxidation phosphorylation system, transfer ribonucleic acids (tRNAs), and ribosomal RNAs (rRNAs). Though mitochondria can replicate independently of the host; nuclear DNA does encode for several mitochondrial proteins. Mutations in mtDNA contribute to some well characterised diseases; mtDNA is also implicated in several diseases and malignancies with poorly elucidated aetiologies. Furthermore, mtDNA can function as a diagnostic tool. Other extra-chromosomal circular DNAs are usually detected in cancer. This review article is intended to provide an overview of four broad categories of small circular DNAs that are present in non-eukaryotic (plasmids and relevant viral genomes) and eukaryotic (mtDNA and other extra-chromosomal DNAs) systems with reference to human diseases, particularly cancer. For this purpose, a literature search has been carried out mainly from PubMed. Improved understanding of the significance of small circular DNA molecules is expected to have far reaching implications in many fields of medicine.