Cytomegalovirus Cure ¦ Treatment and Symptoms
Breast cancer is the leading causes of cancer-related death among women. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. Numerous articles indicate that breast tumors exhibit diverse phenotypes depending on their distinct physiopathological signatures, clinical courses, and therapeutic possibilities.
The human cytomegalovirus HCMV is a multifaceted highly host specific betaherpesvirus that is regarded as asymptomatic or mildly pathogenic virus in immunocompetent host.
HCMV may cause serious in utero infections as well as acute and Cytomegalovirus in der Prostata complications in immunocompromised individual. The involvement of HCMV in late inflammatory complications underscores its possible role in inflammatory diseases and cancer.
HCMV targets a variety of cell types in vivoincluding macrophages, epithelial cells, endothelial cells, fibroblasts, stromal cells, neuronal cells, smooth muscle cells, and hepatocytes.
In this review, we will discuss the potential role of HCMV in the initiation and progression of breast cancer.
Breast cancer is the most frequent cause of cancer-related death among women. According to world health organization more than 5 million deaths have been attributed to breast cancer in Global Health Estimates, WHO Breast cancer represents a heterogeneous disease. Based on the transcriptomic profile, breast tumors have been categorized into at least five Cytomegalovirus in der Prostata subtypes 12.
Information regarding the intrinsic subtype of breast cancer in patients has prognostic significance and may help in designing personalized therapy in future 3. Familial history of breast cancer, hormonal replacement therapies, alcohol consumption, and radiation exposure are few risk factors associated with breast cancer 4.
Biological entities especially viruses are also known to trigger various cancers in human. There are Cytomegalovirus in der Prostata least one dozen of viruses with established role in human malignancies [comprehensively reviewed in Ref. Few viruses are suspected to play a role in the initiation or promotion of breast cancer 6. One of such viruses is human cytomegalovirus HCMV. Human cytomegalovirus also called human herpesvirus 5 is a member of herpesviridae family subfamily betaherpesvirinae.
HCMV infection is either asymptomatic or causes mild discomfort. In certain situations where immunity is either immature or immunocompromised or suppressed, HCMV infection causes significant morbidity and mortality 78.
In the last decade, presence of HCMV genome and antigens has been reported in several kinds of human cancers. These human malignancies include breast cancer, brain cancer, prostate cancer, colon cancer, and salivary gland cancer 9 In addition, we and others Cytomegalovirus in der Prostata shown the oncogenic transforming potential of HCMV in vitro 11 — Several attempts have been made to search for a virus responsible for breast cancer.
InMoore and colleagues examined the milk samples from Cytomegalovirus in der Prostata with or without the history of breast cancer using electron microscopy. With the rapid advancement in DNA and protein technology, presence of several viruses has been detected in breast cancer and normal tissue. However, contrasting findings are also available, which make the relation of viruses and breast cancer highly volatile. A list of viruses Cytomegalovirus in der Prostata could potentially be involved in breast cancer.
Human cytomegalovirus has large protein repertoire that can initiate or promote neoplastic changes in a cell. Richardson hypothesized that incidence of breast cancer could be raised by late exposure to HCMV This hypothesis was based on the incidence of breast cancer and its correlation with the seroprevalence of HCMV.
They enrolled women with invasive breast cancer and controls. Breast milk is the predominant source of HCMV transmission in human. They detected the presence of HCMV antigens specifically in glandular epithelium in surgical biopsies of normal breast, breast with tumor, and normal breast tissue from the breast cancer patients using immunohistochemistry.
Prevalence of HCMV antigens was relatively higher in neoplastic epithelium of patients with breast cancer Cytomegalovirus in der Prostata their study, presence of HCMV antigens was restricted Cytomegalovirus in der Prostata metastatic tumor cells that are not consistent with previous reports 23 There are several reports where no correlation has been found between HCMV and breast cancer. They did not detect the presence of HCMV in any sample They found no significant correlation between HCMV Cytomegalovirus in der Prostata and breast cancer progression.
Variation in tissue handling, sample size, PCR primer designing, and sites of tissue sampling could be responsible for the discrepancy in results among different laboratories Collectively, data from in vitro and in vivo suggest that HCMV may be involved in the initiation or progression of breast cancer. However, in order to obtained conclusive results, clinical findings need to be analyzed on large cohorts and in vitro findings need further validation in animal models.
Human cytomegalovirus is known to infect virtually most organs of the human body including blood, brain, breast, colon, eye, kidney, liver, and lung. Therefore, HCMV exhibits broader tropism. Several reports indicate the replication of HCMV in various cells ranging from monocytes to neural stem cells 2338 — Monocytes and macrophages are widely recognized as important HCMV reservoirs responsible for the dissemination of the virus throughout of the body 41 Prolonged secretion of these cytokines is often linked with the development of cancer [reviewed in Ref.
We have also observed the positive correlation among the seroprevalence of HCMV IgG, elevated IL-6 levels, and incidence of liver cancer in a patient oriented study Hypothetical scheme of HCMV dispersal and its possible involvement in the development of breast cancer. Two potential scenarios could ultimately result in breast tumor after HCMV infection. Subsequently, macrophages present in breast tissue could be also infected by HCMV favoring a protumoral microenvironment.
Upon migration of infected monocytes into breast tissue, HCMV-infected macrophages could transmit the virus to mammary epithelial cells.
M1 macrophages Cytomegalovirus in der Prostata pro-inflammatory cytokines and M2 macrophages secrete immuno-suppressive factors that can promote the progression of breast cancer.
Tumor-associated macrophages TAM that are of poor prognosis during breast cancer and fuel the progression of the disease could be preferentially activated by HCMV. Macrophages associated with the tumorous environment are known as tumor-associated macrophages TAM.
The predominant fractions of TAMs are M2 polarized macrophages. Upon infiltrating tumor surroundings of breast cancer cells, macrophages may acquire M2 state. These M2 macrophages secrete high levels of immunosuppressive cytokines, e.
These M2 macrophages being immunosuppressive in nature indirectly favors the development of breast cancer. For instance, the clinical isolate HCMV-DB displays preferential macrophage tropism, triggers M2 activation state, and stimulates the upregulation of the proto-oncogene Bcl-3 Indeed, TAMs are considered as an important therapeutic target in breast cancer.
Luo and colleagues have identified legumain a stressed molecule overexpressed by TAMs. In Cytomegalovirus in der Prostata, the application of DNA vaccine against legumain has been shown to dramatically reduce tumor angiogenesis in animal model Taken together, these primarily data suggest that the potential route of viral dispersal to breast tissue and involvement of HCMV in breast cancer progression.
Recent Cytomegalovirus in der Prostata reveals the presence of more than translated ORFs 49 in HCMV genome, which is more than double of previous predictions 50 Overview of diverse HCMV proteome involved in modulation of host cell controlled growth. Several members of HCMV proteome have oncogenic properties. Furthermore, we have also observed similar findings in primary human hepatocytes and HepG2 cells Cytomegalovirus in der Prostata HCMV infection Other gene products with oncogenic potential are immediate early IE 1 and IE2.
Data from Spector laboratory further revealed that only viral entry Cytomegalovirus in der Prostata not viral gene expression was prerequisite to induce chromosomal breaks in HFF Taken together, data suggest that the presence of several HCMV proteins that have ability to induce transformation.
Of note, transient or stable expression of a particular viral gene may not truly represent the natural HCMV infection scenario. Rigorous experimentations are needed to elucidate the exact function of these viral proteins in tumor tissue. In breast cancer and HCMV infection, there are several common pathways that are activated.
Therefore, drugs that target these pathways should have significant impact on both HCMV Cytomegalovirus in der Prostata and tumor progression. One of such FDA approved drug is sorafenib, a multi kinase inhibitor that affects several signaling cascades. Sorafenib is known to inhibit the replication of HCMV in several cell types in vitro In a phase II clinical trial involving patients with HER2 negative breast cancer, combination of sorafenib and cepacitabine has been reported to Cytomegalovirus in der Prostata progression free survival in patients Furthermore, phase III clinical trial Clinicaltrials.
Major signaling pathways targeted by HCMV and activated in breast cancer. Signal transducer and activator Cytomegalovirus in der Prostata transcription 3 is an important transcription factor that governs genes responsible for cell cycle progression and apoptosis. Upregulation of pSTAT3 has been reported in several kinds of malignancies including breast cancer Furthermore, exposure of cmvIL to these breast cancer cell lines resulted in increase in cell proliferation and decrease in apoptosis.
In vitro application of these inhibitors has shown to inhibit STAT3 activation, cell invasion, and colony formation in breast cancer cell lines Even results were promising in animal models. Same group has recently developed another STAT3 inhibitor termed BP that represses the tumor growth of breast cancer cells in xenografts Another important signaling axis pertaining to homeostasis is PI3K—Akt axis.
PI3K driven signaling cascades play an important role in cell growth, differentiation, glucose metabolism, and chemotaxis In breast cancer, aberrant expression of PI3K and its downstream signaling partners is frequently observed.
However, impact of these inhibitors in HCMV replication is not assessed. In addition to above mentioned signaling pathways, impact of HCMV infection on Wnt pathway has been investigated 81 In addition, treatment of cells with Wnt Cytomegalovirus in der Prostata monensin, nigericin, and salinomycin resulted in inhibition of HCMV replication in fibroblasts, suggesting important role of Wnt signaling partners in HCMV replication.
Wnt plays important role in cell growth, cell fate determination, and tumorigenesis. Upregulation of Wnt pathway genes have been observed in breast cancer cell lines and patient samples Collectively, this makes Wnt pathways an attractive tool in targeting HCMV and breast cancerous cells simultaneously.
For example, XAV a small molecule tankyrase inhibitor has been shown to attenuate Wnt pathways in several breast cancer cell lines Development of resistance against a particular drug during cancer progression is frequent.
Therefore, there is need to formulate feasible combinatorial therapies against breast cancer.