Corresponding Author: Liborija Lugović-Mihić
Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Vinogradska cesta 29, 10 000 Zagreb (Croatia)
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The Influence of Psychological Stress on HPV Infection Manifestations and Carcinogenesis
Liborija Lugović-Mihića,b Hrvoje Cvitanovićc Ivka Djakovićd Matea Kunaa,b Ana Šešerkoe
aDepartment of Dermatovenereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia, bSchool of Dental Medicine, University of Zagreb, Zagreb, Croatia, cDepartment of Dermatovenereology, Karlovac General Hospital, Karlovac, Croatia, dDepartment of of Gynaecology and Obstetrics, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia, eDepartment of Gynaecology and Obstetrics, University Hospital Center Zagreb, Zagreb, Croatia
Psychological stress is an important factor involved in disease manifestations of HPV infection, and it can participate in carcinogenesis associated with HPV. Due to inconsistencies in some study results, this issue remains a subject of research. It is important to determine to what extent stress plays a role in HPV manifestations and carcinogenesis and how much it participates in the onset, development, and progression of infections.
Features of HPV
Human papillomavirus (HPV) is a DNA virus that belongs to the Papillomaviridae family. It is one of the most ubiquitous viral infections in humans, and it usually manifests as skin or genital mucosa lesions, although it can occur in other mucosa as well. It has long been known that most sexually active people will be infected by this virus at some point of their life, and the incidence of HPV infection is highest in the age group for those 20-40 years old [1-4]. Despite its high prevalence, most who get infected will not have a clinically overt infection. Still, the persistence of the HPV infection may cause a higher risk for developing cervical intraepithelial neoplasia (CIN) and invasive carcinoma. In women, a breakout from a high-risk HPV infection typically takes 14 months to clear up for an oncogenic infection and 5-6 months for a non-oncogenic infection .
To date, more than 200 types of HPV have been identified . A strain is considered new when the nucleotides of the L1 part of the HPV genome differ from that of known HPV viruses by more than 10% [6, 7]. HPV viruses can be divided into different groups by their affinity for certain tissues, which in some part depends on their genotype . The specific skin lesions for each type of HPV are as follows: common warts – types 2, 7, 22; plantar warts – types 1, 2, 4, 63; flat warts – types 3, 10, 28; and for verrucous cyst type 60 and epidermodysplasia verruciformis - more than 15 different types. There are also specific HPV types for anal/genital manifestations: anogenital warts—types 6, 11, 42, 44 and others; anal dysplasia (lesions) – types 16, 18, 31, 53, 58; and genital cancers— highest risk types 16, 18, 31, 45, other high-risk types— 33, 35, 39, 51, 52, 56, 58, 59, and probably high-risk— types 26, 53, 66, 68, 73, 82 . The types of HPV for oral/oropharingeal lesions are: focal epithelial hyperplasia (mouth)—types 13 and 32; mouth papillomas—types 6, 7, 11, 16, 32); and oropharyngeal cancer—type 16; laryngeal papillomatosis—types 6 and 11 . Concerning oncogenic risk, the low-risk HPV types are 6, 11, 49, 42, 43, 44, 54, 61, 70, 72 and 81, while the high-risk types are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. In addition, 60% of all genital warts are caused by HPV types 16 and 11 .
HPV is transmitted through direct skin or mucous membrane contact, and infection can be clinical, subclinical or latent. Microimpairments in the skin or mucous membrane enhance transmission, but for infection to develop it is essential for the complete virus to be transmitted, not only its DNA fragments . In the sexually active population, HPV is present in 80% of women of reproductive age, but its manifestations resolve spontaneously in most cases (cca 80 % of infections) within 12-24 months . Untreated HPV manifestations in men can cause invasive penile carcinoma, which represents 1% of malignancies in men in developed countries and 10-20% in undeveloped countries. In men, incidence of death due to suffering from HPV-associated cancers of different organs is 0.32 per 100.000 .
HPV is a double-stranded DNA virus that has an icosahedron shape and a double-layered capsid made of 72 capsomers (HPV’s capsid is not covered by a lipid membrane, which makes it resistant to ethanol and solvents.) It has 8,000 base pairs with a molecular mass of 5200 kDa [8, 11]. The genes are divided into two groups: early (E) and late (L). The group of early genes is composed of six genes (E1, E2, E4, E5, E6, E7) that code for the proteins responsible for replication, transcription, and malignant transformation [5, 8, 11]. Late genes L1 and L2 code for the viral envelope (non-lipid membrane) and for the proteins responsible for the capsid’s structure. Gene L1 is the oldest, and it is used to identify the different types of HPV. A 10% difference in the nucleotide sequence of the L1 gene signifies a new strain (type), while a difference of 2-10% is considered a subtype, and a difference of less than 2% is defined as a variant.
The oncogenic potential of HPV depends on genes E6 and E7. The product of the E6 gene binds to the p53 oncosupressor, and the product of E7 binds to the RB protein. In the case of cervical intraepithelial neoplasia, genes of high-risk types are integrated into the DNA of the host. This integration in some cases leads to disruption of the E2 gene, which results in increased replication of the E6 and E7 genes. The E6 protein binds to p53 causing it to degrade. The E7 protein inactivates the RB protein so that E2F proteins detach from the RB, preventing transcription of the gene that regulates cell growth and differentiation [5, 11]. It has been established that E6 and E7 interfere with the immune response by reducing production of interferon (IFN) . Therefore, the E1 and E2 genes of HPVs are involved in viral replication, while the E6 and E7 proteins function as the promotors of proliferation. The major HPV oncogenes are E6 and E7, which disrupt the normal regulation of the cell cycle and cell progression, giving them an important role in the oncogenesis of HPVs with a high risk of causing anogenital and cervical cancer. Immortalization of epithelial cells induced by HPV requires viral DNA integration into the host cell genome, which causes disruption of the E2 gene. The E2 protein is also a transcription factor, which regulates expression of the E6 and E7 oncoproteins. Integration of the virus in the human genome disrupts the E2 gene and increases expression of E6 and E7 genes in vitro [12-21].
Concerning molecular events during the progression of cervical lesions to carcinogenic lesions, persistent high-risk HPV infection leads to integration of HPV into the host genome and to overexpression of oncogenes E6 and E7 . On the molecular level, interaction of Е7 with the pRb protein leads to aberrant initiation of the S-phase. The E7 oncoprotein causes release of E2F transcription factor from the pRb protein, which is then active and can initiate transcription of genes involved in cell cycle progression, contributing to cellular immortalization and transformation. Thus, Е6 targets р53 for proteasomal degradation, which leads to inhibition of apoptosis and DNA repair (anti-apoptotic effect). It is important to emphasize that only high-risk HPV types can induce degradation of p53, which can then lead to carcinogenesis. E6 activates the PI3K/Akt pathway, interacts with cellular proteins NFX1, and induces human telomerase reverse transcriptase (hTERT) activation, leading to immortalization and transformation. The interaction of both oncoproteins with DNA methyl transferases leads to aberrant methylation, causing silencing of tumor suppressor genes. Also, E7 interaction with histone deacetylases (HDACs) causes chromosome remodelling and genome instability. So, during lesional progression to carcinogenesis, the cross interaction of E6 and E7 with various pathways plays the crucial role . It is also important to mention that viruses like HPV can create virions and become transmissible at any point in their life cycle (the productive virus replication also known as lytic replication). When lytic replication of the virus begins, it is almost irreversible, and successful replication of the virus begins as well as host cell death. But in tumor cells, these infections are mostly latent, allowing the virus to evade the immune response. Thus, lytic replication of the virus is reduced or absent in the tumor. In viral latency there in no production of unnecessary viral proteins that could initiate cell mediated immune recognition. Integration of the viral genome into the host genome eliminates the virus’s ability to replicate as virions, but the virus can replicate using the host’s cellular mechanisms and can be divided whenever the host cell divides. By evading apoptosis, as previously described, oncogenesis begins . All this indicates that a complex network of actions is involved in the pathogenesis process during the occurrence of HPV manifestations.
Stress, types of stressors, the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic autonomic nervous system (ANS) and the impact of stress on the body and disease
Stress is defined as physical or mental exertion caused by factors that change homeostasis, and it can be observed as an objective stimulus, as an organism’s response to stimulus, or as a relation between a person and their surrounding environment. Stress is a state of threat to physical, psychological, and social homeostasis. More recent approaches define stress as any stimulus that causes sudden termination of ordinary activities, that is, an event that goes beyond what is normal for the organism. The impact or effect, which stress can have, depends on a person’s genetic pool, experiences, and behaviors [24-28]. The biopsychosocial model of disease and health, for example, asserts that biological, psychological and social factors interdependently affect the course and outcome of disease (Fig. 1). Psychological stress has become an increasingly important factor in the course of disease, due especially to the circumstances of modern life .
Stressors can be physical, chemical, psychological and biological. Psychological and social strains are the most common stressors . Stress can be categorized by duration (acute or chronic), relevance (avoidable/averted or unavoidable), and intensity (mild, moderate, or severe). Aside from stress caused by common life events, there are also big traumatic events such as war, a natural disaster, death in the family, job loss, etc. Psych trauma is a state of high-level stress that can result in posttraumatic stress disorder (PTSD) and can cause long-lasting health problems. In physical, chemical, and biological stress, the condition of the person is determined by the harm caused by an external stimulus, whereas in psychological stress, one’s assessment of environmental dangers, threats or challenges is the important factor. Stress in humans usually manifests through physical symptoms (e.g. palpitations, shortness of breath, perspiration, angina pectoris, frequent infections) or psychological symptoms (e.g. indecisiveness, poor concentration and memory loss, high sensitivity, sleep disturbances, negative thoughts). As a result, stress-related illnesses can occur (e.g. gastric ulcer, hypertension, viral infection, myocardial infarction, psoriasis, allergies, asthma, anxiety disorders, tumors, gastrointestinal disorders) [26-28].
When stressed, the organism reacts in a stress-adapting manner that can take place at the cell-, organ- or organ-system level, or at the level of the entire organism . The organism typically reacts in three phases to a threat or injury with the same set of reactions outlined by the General Adaptation Syndrome (GAS): (1.) alarm; (2.) resistance; and (3.) exhaustion, the long-lasting debilitating phase that makes one susceptible to disease onset . When reacting to external and internal demands by modulating functions and adapting to new conditions (referred to as alostasis), system stability can be achieved through constant adaptation. The main adaptive system includes the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic autonomic nervous system, and cytokine production (Fig. 2) [19-22]. Pathogenetically, the body neutralizes stress with a complex network of physiologic and behavioral responses to reestablish optimal body equilibrium (eustasis) . As crucial components of the stress response, the HPA axis and the autonomic nervous system (ANS) interact with other vital centers in the central nervous system (CNS) and peripheral tissues/organs to mobilize an adequate/appropriate adaptive response against stressors. Thus, different stressful events are recognised by the hypothalamic paraventricular nucleus, which participates in a biological circuit that integrates personal experiences, physiological signalling and the release of corticotropin-releasing hormone (CRH) . CRH acts on the pituitary gland, which then releases adrenocorticotropic hormone (ACTH), followed by ACTH signals to the adrenal cortex to release glucocorticoids . Thus, the body’s adaptive stress response depends on many interconnected neuroendocrine, immune, cellular, and molecular mechanisms.
During stress, the brain and CNS are the main actors; their response includes a variety of crucial neuroendocrine and autonomic reactions in order to achieve homeostasis [25-28, 32-35]. During that process, neurogenic stressors activate processes in the CNS. Signals are then transferred to periventricular nuclei from prefrontal cortex and limbic structures, where stress is compared to experiential events. This processed signal is transferred to the hypothalamus, which in turn activates the HPA axis. Hypothalamic nuclei receive stimuli from limbic and brain stem catecholaminergic signalling pathways. Periventricular nuclei can be activated by locus ceruleus aminergic signals. Central, medial and cortical amygdala nuclei are connected to periventricular and gabaergic neurons forming a closed circle. Activation of glutaminergic neurons stimulates the hypothalamic release of CRH in the eminentia mediana, which then reaches the hypophysis (anterior pituitary) through portal circulation and stimulates the release of ACTH into the peripheral circulation. Activation of the sympathetic nervous system causes terminal nerves and adrenal gland medulla to secret more catecholamines [36, 37]. The immune system affects the brain as well; thus, there is a bilateral connection. It is important to emphasize that ACTH stimulates the release of glucocorticoids from the adrenal glands, meaning cortisol is a main stress hormone. Sympatho-adrenomedullary axis (SAM) activation stimulates CRH secretion in the hypothalamic periventricular neuron (PVN) area [25-28, 38]. Stress enhances the activities of many systems and releasing of various substances, including catecholamines, opiates and corticosteroids, which have an immunosuppressive effect by decreasing activity of cytokines and inflammation. It has been shown that immune cells have hormone receptors (corticosteroid, prolactin, growth hormone, sex hormones), neuropeptide receptors (endorphins, vasoactive intestinal peptide, substance P, etc.) and neurotransmitter receptors (adrenaline, noradrenaline, acetylcholine, serotonin, etc.). During acute stress, posterior hypothalamic nuclei, the sympathetic nervous system and adrenal gland medulla are activated, while in chronic stress, the anterior hypothalamus, sympathetic system and adrenal gland cortex are activated.
Finally, the release of glucocorticoids, mainly cortisol, is followed by increased lipolysis and gluconeogenesis to supply the body with available energy sources. A negative feedback system regulates production of cortisol via the hypothalamus and pituitary glands. In addition, the sympathetic nervous system (SNS) is activated and stimulates the adrenal medulla to release catecholamines, adrenaline and noradrenaline, allowing the body’s systems to transport energy to the organs more quickly. Consequently, homeostasis is re-established, provided the stressor falls into the adaptive capacity . However, during severe and/or chronic stress, dysregulation of the stress system (hyperactivation or hypoactivation) can disrupt homeostasis and lead to cacostasis or allostasis with possible various clinical manifestations . Prolonged activation of stress mechanisms with increased glucocorticoid and catecholamine levels causes a condition where the demand on the individual exceeds their personal adaptive capacity (allostatic load). Therefore, according to research results, chronic stress and increased glucocorticoid/catecholamine levels may participate in cancer progression in different diseases, including HPV-related carcinogenesis .
It is significant that cortisol, as the main stress hormone, modifies apoptosis and changes the way in which cytokines are secreted. It is assumed that exposure to relevant stress events can result in dysregulation of the sensitivity and numbers of glucocorticoid receptors (GCR), and that cortisol can affect secretion of local cytokines and trigger stronger inflammation [25, 27, 39]. Glucocorticoids exert their effects through two subtypes of intracellular receptors: (type I) GCR with a high affinity for endogenous corticosteroids (that has a regulating function over the circadian rhythm of the HPA axis) and (type II) GCR with a lower affinity (important for acute stress reactions). In the nucleus, glucocorticoid acts as a transcription factor, and it binds to specific DNA sequences named glucocorticoid response elements (GRE). These sequences modulate gene transcription. Glucocorticoids also interact with other transcription factors, such as AP-1 (activator protein 1) and NF-κB (nuclear factor kappa B). During a stress inflammatory response, glucocorticoids decrease secretion of proinflammatory cytokines and increase secretion of anti-inflammatory cytokines. They also affect redistribution of leukocytes and decrease synthesis and expression of cytokine receptors, lymphocyte proliferation and adhesion molecule expression on the cell surface.
Finally, in stress, adaptive reactions involve the short-term activation of the HPA axis, whereas overproduction of stress hormones and disruption of the regulation of the HPA axis triggers a pathological response/reaction. Just as the cognitive perception of stress is important, so is coping, defined as the constant adaptation of cognitive and behavioral efforts to overcome demands that one finds overwhelming. Adaptive coping styles are usually related to positive personality characteristics, while maladaptive styles are linked to less desireable characteristics. The coping styles a person uses depend primarily upon the situation but also on the disposition of the person themselves.
We would like to express our heartfelt gratitude to Mrs. Suzana Salopek for her selfless help and valuable assistance.
LLM contributed conception and design of the article; LLM, HC, MK and AŠ analyzed the data; LLM, HC and ID wrote the manuscript; all authors contributed to manuscript revision, read and approved the submitted version.
Statement of Ethics
The authors have no ethical conflicts to disclose.
The authors declare that no conflicts of interest exist.
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