Nasopharyngeal nay-zoh-fuh-RIN-jee-ul carcinoma is cancer that occurs in the nasopharynx, which is located behind your nose and above the back of your throat. Nasopharyngeal carcinoma is rare in the United States. It occurs much more frequently in other parts of the world — specifically Southeast Asia. Nasopharyngeal carcinoma is difficult to detect early. That's probably because the nasopharynx isn't easy to examine and symptoms of nasopharyngeal carcinoma mimic those of other, more-common conditions.
Treatment for nasopharyngeal carcinoma usually involves radiation therapy, chemotherapy or a combination of the two. You can work with your doctor to determine the exact approach depending on your particular situation.
In its early stages, nasopharyngeal carcinoma may not cause any symptoms. Possible noticeable symptoms of nasopharyngeal carcinoma include:. Early nasopharyngeal carcinoma symptoms may not always prompt you to see your doctor.
However, if you notice any unusual and persistent changes in your body that don't seem right to you, such as unusual nasal congestion, see your doctor. There is a problem with information submitted for this request.
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Subsequently, cellular kinases catalyze the formation of the cytotoxic diphosphate and triphosphate forms of the drugs. These cytotoxic drugs incorporate into the lytic cells, resulting in apoptosis. Apoptotic cells break down and release the toxic drugs to the tumor microenvironment.
Adjacent latent cancer cells absorb the released drugs the bystander effect and are eradicated by them. This bystander effect then further promotes tumor shrinkage.
In lymphocytes, EBV establishes a life-long latency stage upon infection, while it frequently undergoes lytic replication in the epithelial cells of healthy carriers. This is consistent with the fact that primary EBV infection takes place at the oral epithelium, after which the lytic infection of oral epithelial cells triggers the release of infectious virions that infect the surrounding B lymphocytes 6 , This shows that the latent-lytic switch in NPC cells is tightly regulated by both viral latent genes and cellular factors.
Epigenetic modification of the viral genome, cellular transcription repressors, and a number of EBV-encoded microRNAs have been shown to contribute to inhibiting lytic gene expression 93 — Nevertheless, the effects of these cellular factors on lytic-cycle induction remain to be defined in EBV-positive NPC cells. BZLF1 and BRLF1 proteins are able to activate both their own and one another's promoters, resulting in efficient lytic-cycle induction.
BZLF1 preferentially activates lytic promoters that are methylated, whereas BRLF1 preferentially activates unmethylated lytic promoters 92 , Thus, the ability of EBV to switch from latent to lytic infection is largely determined by the presence of cellular transcriptional activators that stimulate Zp or Rp, and the inactivation of cellular transcriptional repressors that simultaneously suppress Zp or Rp The late genes encoding structural proteins viral capsid antigen and gp are expressed after viral genome replication, to assist EBV virion production 97 — This observation strongly supports the potential clinical application of lytic induction therapy in NPC patients.
To this end, multiple preclinical and clinical studies have been conducted over the past two decades to explore various lytic cycle-inducing agents for cytolytic reactivation therapy in EBV-associated NPC. These lytic inducers include chemotherapeutic agents, phorbol esters, histone deacetylase inhibitors HDACis , and a number of novel chemical compounds identified by large-scale screening studies Figure 4 , Table 2. Figure 4. Schematic diagram showing the rationales of lytic induction treatment of EBV-associated cancers.
Multiple classes of chemical inducer trigger EBV lytic induction via activating different cellular signaling pathways with extensive cross-talks.
The expression of IE proteins further induces the early lytic proteins BGLF4 protein kinase and BXLF1 thymidine kinase which convert the ganciclovir into cytotoxic drugs to kill cancer cells during the cytolytic treatment.
Table 2. Several FDA-approved drugs for chemotherapy show cell-context-specific ability to switch latency to the lytic cycle in EBV-infected cells.
The combination of gemcitabine and VPA showed a synergistic effect on inducing expression of EBV lytic gene expression, while inclusion of GCV further enhanced the cytotoxicity in the tumor cells. A pilot clinical study of CLVA therapy revealed that the treatment was well-tolerated and resulted in disease stabilization and improved quality of life in three patients with progressive end-stage NPC These findings show that clinical benefit of CLVA treatment needs further evaluation in large-scale clinical studies that include a patient group receiving gemcitabine treatment only.
The gross change of histone acetylation status in a particular gene locus is due to the respective activities of histone deacetylases HDACs and histone acetyltransferases HATs : HDACs deacetylate histones and other non-histone proteins, while HATs catalyze the transfer of acetyl groups from acetyl coenzyme A to the lysine residues of proteins. Both act as cofactors of different transcription regulators for modifying chromatin structure. The HDACis are categorized into five groups according to their structure: that is, cyclic peptides, hydroxamic acids, benzamides, short-chain fatty acids, and sirtuin inhibitors Among the HDACis investigated in EBV-positive epithelial cancer cell lines, suberoylanilide hydroxamic acid SAHA , alone or in combination with a proteasome inhibitor bortezomib , was found to be superior in terms of inducing EBV reactivation and causing cancer cell death , Notably, the combined treatment of bortezomib and SAHA enhanced ROS production, which caused cell apoptosis and at the same time suppressed virion production , Although HDACi treatments are effective in triggering EBV reactivation in particular cell line models, their broad efficacy in cell line models remains in doubt, as varied ability of HDACis to trigger EBV reactivation in different cell lines has been highlighted recently Moreover, the underlying mechanisms of the induction of IE genes by these treatments have generally not been investigated and therefore remain elusive.
Although it is believed that the opened chromatin structures of IE promoters are critical for their induction, gene transcription does not occur efficiently unless transcription repressors are displaced from the IE promoters. Furthermore, SAHA is known to alter the acetylation of non-histone proteins as well Thus, it is conceivable that understanding the acetylation status of other non-histone proteins will be critical to solve the discrepancy between different studies using HDACis.
As TPA is a classical tumor-promoting agent and can cause skin carcinogenesis , it is intrinsically unsuitable as a clinical drug. Nevertheless, other clinically approved PKC activators are worth exploring for their potential ability to induce the lytic cycle in NPC cells.
Five compounds showed dose-dependent induction of EBV lytic genes at micromolar concentrations and specific cytotoxicity in EBV-infected epithelial cells. As C7 contains a metal-binding moiety and functions as a chelator of intracellular iron, the group has further examined the ability of other iron chelators, such as Dp44mT, deferoxamine, deferiprone, and deferasirox, to reactivate the EBV lytic cycle in EBV-positive epithelial cancers.
Thus, iron chelators appear to activate hypoxic signaling and autophagy to trigger lytic reactivation in EBV-positive epithelial cancer cells The above studies have identified the clinically available iron chelators as a novel class of lytic inducer for potential cytolytic therapy.
Due to the importance of cellular factors in the regulation of the latent-lytic switch in EBV, the response of NPC cells to different classes of lytic inducers is believed to be cell-context-specific. Specifically, NPC cells in each individual tumor might evolve and acquire different somatic changes to ensure EBV latency during cancer progression. Recent genomic studies have also revealed that a number of somatic alterations e.
The use of more genomically characterized patient-derived NPC models and native EBV-infected cell lines in comprehensive studies on the association of somatic genetic changes in these tumors with their response to different classes of chemical inducer may allow us to develop effective cytolytic treatment strategies for NPC patients 24 , In addition, uncovering the cellular mechanisms of the resistance of tumor cells to lytic cycle induction is important for improving the efficacy of this treatment.
However, the roles of these NPC-associated oncogenic-signaling pathways in the switching of persistent latent infection to the lytic cycle have not been defined. The combination treatment of EBV lytic inducers with selected targeted inhibitors of these specific pathways in EBV-positive NPC tumors may provide new insights on the cellular signals that regulate lytic reactivation.
Finally, the high expression of multiple immunogenic viral lytic antigens during EBV lytic reactivation is expected to raise potent immune responses during cytolytic therapy. It is interested to elucidate the effect of cytolytic therapy on the host immune surveillance by comprehensively characterizing the tumor microenvironment in NPC humanized mouse models. The findings will enhance our outstanding of the host immune response to EBV targeting treatment.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Focus on nasopharyngeal carcinoma. Cancer Cell. Nasopharyngeal carcinoma. Translational genomics of nasopharyngeal cancer.
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