Understanding Nasopharyngeal Carcinoma

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
Introduction
Understanding Biomarkers in Nasopharyngeal Carcinoma
Research on Natural Compounds which may be Suppressive Against Nasopharyngeal Carcinoma
References

Introduction
Nasopharyngeal carcinoma (NPC) is a squamous epithelial cancer arising from the lateral wall surface of the nasopharynx. According to the world health organization, NPC can be classified into 3 subtypes of microscopic histological patterns. These include (i) type I, keratinizing squamous cell carcinoma that shows predominant features of producing keratin proteins, (ii) type II, differentiated nonkeratinizing carcinoma, and (iii) type III, nonkeratinizing carcinoma with less differentiation. While the NPC type I is uncommon in endemic areas, types II and III are more common and have been shown to be closely related to EBV infection. There are lines of evidence showing that EBV plays a critical role in transforming nasopharyngeal epithelial cells into invasive cancer cells. (Tulalamba & Janvilisri 2012)

At present, treatment of NPC is usually via radiotherapy. NPC is more sensitive to ionizing radiation than other cancers. However, the treatment success mostly depends on the tumor, node, and metastasis (TNM) stages classification, which tend to be in the advanced stages at the point of diagnosis because the primary anatomical site of cancer growth is located in the silent painless area. (Tulalamba & Janvilisri 2012)

Retrospective studies that used radiotherapy (RT) alone for NPC indicated that local control was closely linked to the radiation dose delivered to target tissues. Intensity modulated RT (IMRT) is a special type of conformal RT that creates a high dose volume that is precisely shaped around the target volume in order to minimize the radiation dose delivered to surrounding healthy tissues. Investigators compared dosimetric plans of IMRT with conventional RT techniques and concluded that IMRT provided improved tumor coverage and preservation of normal tissues. The proximity of the nasopharynx to critical normal tissues, such as the brainstem and optic structures, makes it challenging for radiotherapists to deliver the optimal radiation dose to the tumor using conventional conformal RT, and underdosing of affected areas is often necessary to preserve healthy tissues. IMRT for locally advanced NPC spares critical portions of the brain stem and of the parotid glands, avoiding neurologic toxicity and permanent xerostomia (dry mouth), respectively. While IMRT has completely replaced conventional conformal RT and has become the standard practice for early stage NPC, its role in the locally advanced setting is not yet well defined. (Perri et al 2011)

The mechanism of NPC tumorigenesis is complex, involving the aberrations of a large variety of pathways and the alteration in expression of numerous proteins. Normal regulation of apoptosis, cell proliferation, and cell adhesion are dysregulated. The understanding of these mechanisms has greatly increased in the past decade, generating enough data to begin the development of prognostic factors and targeted treatments for NPC. (Chou et al 2008)

In NPC there is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E-cadherin and β-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments. (Chou et al 2008)

Understanding Biomarkers in Nasopharyngeal Carcinoma
Bcl-2 – This study provides proof of principle that TRAIL (Tumor necrosis factor-related apoptosis inducing ligand) combined with simultaneously targeting the Bcl-2 and Akt signaling pathways may have potential as a novel future treatment strategy for NPC. (Li et al 2011)

E-cadherin – Our studies provide convincing evidence that EMT may play an important role in the biological progression of NPC, and nuclear vimentin and cytoplasmic E-cadherin might have independent prognostic value in NPC patients and serve as novel targets for prognostic therapeutics. (Luo et al 2012)

EGFR – EGFR/ErbB1 expression is detected in the majority of NPC tumors with advanced disease. (Bourouba et al 2011)

HLA-G –  Taken together, our results suggest that Human leukocyte antigen G (HLA-G) is an independent biomarker for NPC prognosis, and HLA-G might contribute to NPC progression, which might jointly regulate immune surveillance in NPC together with macrophages and IL-10. (Cai et al 2012)

KRAS – We observed substantial upregulation of KRAS protein in NPC tissues, and KRAS protein levels were inversely correlated with miR-216b levels. (Deng et al 2011) 

LMP1 – expression is positively associated with metastasis in NPC, thus LMP1 detection in primary NPC might be an effective and feasible means to predict metastasis. (Zhao et al 2012)

MMP-9  – High level of MMP9 expression is a potential unfavorable prognostic factor for patients with NPC. (Liu et al 2010)

mTOR – Histologically, the nasopharyngeal tissue is lympho-epithelial, rich of resident and transient B cells. This confers a distinct and unique micro-environment for carcinomas predicated primarily on the immunoregulatory role of B cells. Recent evidence supports this working model by Super Mario suggesting that Akt emits two mutually counter-balancing signals in regulating B cell differentiation and apoptosis: one involves mTOR activation, and the other remains to be elucidated. (Oluwadara et al 2011) 

N-cadherin – Nuclear N-cadherin expression may represent a valuable prognostic marker in NPC patients, especially those with late stage disease. (Luo et al 2012)

NF-κB – Id-1 expression is a novel independent prognostic marker molecule that helps identify NPC patients with a poor prognosis. Additionally, combined analysis of Id-1 and NF-κB/p65 can be useful for identifying patients at risk for unfavorable clinical outcomes. Id-1 or/and NF-κB/p65 enhanced tumor cell migration, which is associated with the secretion of MMP-9. (Sun et al 2012)

p16 & p53 – A tumor suppressor gene p53 is mostly intact and overexpressed in NPC whereas expression of p16, a cyclin-dependent kinase inhibitory protein, is downregulated in 2/3 of NPC. (Yoshizaki et al 2012)

PTEN – Significantly, immunohistochemistry studies demonstrate that PTEN is downregulated at late stages of NPC, and that miR-205 is significantly elevated followed the radiotherapy. Our data conclude that miR-205 contributes to radioresistance of NPC by directly targeting PTEN. Both  miR-205 and PTEN are potential predictive biomarkers for radiosensitivity of NPC and may serve as targets for achieve successful radiotherapy in NPC. (Qu et al 2012)

SPARC – expression is common in NPC patients. Our data shows that elevated SPARC expression is a potential unfavorable prognostic factor for patients with NPC. (Wang et al 2012)

TNF-α – High expression levels of sCCL2 and sTNF-α predict bone invasion, post-treatment distant metastasis and poor overall survival in NPC patients. (Lu et al 2011)

Tumor hypoxia – Studies published to date showed that tumor hypoxia is common in NPC and it is associated with disease progression and resistance to therapy. Several mechanisms have been proposed on the role of tumor hypoxia in NPC cell survival, angiogenesis, and metabolism. Studies reported by us and by others have demonstrated the therapeutic potential of targeting tumor hypoxia in اكشن من NPC. (Hong et al 2011)

VEGF  & MMP2 and MMP9 – The anti-cancer action of zoledronic acid was partially associated with the suppression of VEGF expression and secretion and downregulating the expression of MMP2 and MMP9. (Li et al 2012)

Research on Natural Compounds which may be Suppressive Against Nasopharyngeal Carcinoma 
Aloe-emodin (AE), (extracted from the rhizome of Rheum palmatum) – our results indicate that AE inhibits invasion of NPC cells by suppressing the expression of MMP-2 via the p38 MAPK-NF-kappaB signaling pathway. (Lin et al 2010)

Astragalus – The combination of CDDP + Astragalus could be developed as an effective chemotherapeutic regimen in the treatment of nasopharyngeal carcinoma. (Song et al 2011) 

Curcumin – The findings demonstrate that the presence of curcumin significantly enhances the ultrasound-induced cell death and ROS level, and induces the collapse of ΔΨm, suggesting that ultrasound sonication can increase the cell death of NPC cells in the presence of curcumin and that the treatment using curcumin and ultrasound together is a potential therapeutic modality in the management of malignant tumors. (Wang et al 2011)

EGCG inhibited the survival rate of NPC cells and induced apoptosis of NPC cells via the mitochondrial signal transduction pathway. This study suggests that the interference effect of EGCG on targets of the mitochondrial signal transduction pathway plays an important role in the anticancer function. (Zho et al 2004) 

Genistein – We found that genistein dose-dependently inhibited the proliferation of human NPC cell line CNE2 cells. (Han et al 2010)

Grape seed proanthocyanidins – These results indicate that grape seed proanthocyanidins (GSPs) have the ability to inhibit  Head and neck squamous cell carcinoma HNSCC cell invasion, and do so by targeting the expression of EGFR and activation of NF-κB as well as inhibiting the epithelial-to-mesenchymal transition. (Sun et al 2012)

Resveratrol – Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria, and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment. (Huang et al 2011)

Ursolic acid –The in vitro cytotoxic efficacy of 15 triterpenes was investigated using three human cancer cell lines, namely, HONE-1 nasopharyngeal carcinoma, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells. Compound 8 and pentacyclic triterpenes 9-15 [ursolic acid (14)] possessing a carboxylic acid functionality at C-28 showed significant cytotoxic activities against the aforementioned cell lines and gave IC50 values in the range 4.0-9.4 microM. (Chiang et al 2005) 

References
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Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257
Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281
Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006
McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002
Mills, Simon and Kerry Bone, Principles and Practice of Phytotherapy, Churchill Livingstone, Edinburgh, 2000
Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009
Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008
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Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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