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Systemic disease-induced salivary biomarker profiles in mouse models of melanoma and non-small cell lung cancer.

Gao K, Zhou H, Zhang L, Lee JW, Zhou Q, Hu S, Wolinsky LE, Farrell J, Eibl G, Wong DT - PLoS ONE (2009)

Bottom Line: Saliva (oral fluids) is an emerging biofluid poised for detection of clinical diseases.Taken together, our data support the conclusion that upon systemic disease development, significant changes can occur in the salivary biomarker profile.Although the origins of the disease-induced salivary biomarkers may be both systemic and local, stimulation of salivary gland by mediators released from remote tumors plays an important role in regulating the salivary surrogate biomarker profiles.

View Article: PubMed Central - PubMed

Affiliation: School of Dentistry & Dental Research Institute, University of California Los Angeles, Los Angeles, CA, USA.

ABSTRACT

Background: Saliva (oral fluids) is an emerging biofluid poised for detection of clinical diseases. Although the rationale for oral diseases applications (e.g. oral cancer) is intuitive, the rationale and relationship between systemic diseases and saliva biomarkers are unclear.

Methodology/principal findings: In this study, we used mouse models of melanoma and non-small cell lung cancer and compared the transcriptome biomarker profiles of tumor-bearing mice to those of control mice. Microarray analysis showed that salivary transcriptomes were significantly altered in tumor-bearing mice vs. controls. Significant overlapping among transcriptomes of mouse tumors, serum, salivary glands and saliva suggests that salivary biomarkers have multiple origins. Furthermore, we identified that the expression of two groups of significantly altered transcription factors (TFs) Runx1, Mlxipl, Trim30 and Egr1, Tbx1, Nr1d1 in salivary gland tissue of melanoma-bearing mice can potentially be responsible for 82.6% of the up-regulated gene expression and 62.5% of the down-regulated gene expression, respectively, in the saliva of melanoma-bearing mice. We also showed that the ectopic production of nerve growth factor (NGF) in the melanoma tumor tissue as a tumor-released mediator can induce expression of the TF Egr-1 in the salivary gland.

Conclusions: Taken together, our data support the conclusion that upon systemic disease development, significant changes can occur in the salivary biomarker profile. Although the origins of the disease-induced salivary biomarkers may be both systemic and local, stimulation of salivary gland by mediators released from remote tumors plays an important role in regulating the salivary surrogate biomarker profiles.

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Related in: MedlinePlus

The working model: The relationship between the salivary transcriptome and the remote tumor.Mediators such as NGF secreted by remote tumors are transferred to salivary gland through blood to stimulate TFs expression and alter salivary mRNA profile.
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pone-0005875-g006: The working model: The relationship between the salivary transcriptome and the remote tumor.Mediators such as NGF secreted by remote tumors are transferred to salivary gland through blood to stimulate TFs expression and alter salivary mRNA profile.

Mentions: Since the induction of TFs expression in the salivary glands occurred in mice with a distal tumor, we further hypothesized there are tumor-specific mediators that can effect the altered TG expression in the salivary glands. It is well-known that tumors ectopically express mediators that have systemic effects on distal organs and facilitate metastasis of cancer cells [26], [27]. Melanomas are known to ectopically express TGF-beta [28] while lung tumors ectopically express gonadotropins and other hormones [29], [30]. We investigated if one such signaling pathway can related to one of the identified TFs that can be responsible for induction or suppression of the salivary transcriptome in the mouse melanoma model. Indeed, NGF is known to stimulate expression of the TF Egr-1 through a well-studied signaling pathway (Fig. 5A). Using an NGF ELISA assay, we observed that the concentration of NGF in melanoma tissue and serum is significantly higher than in counterpart control tissues (Fig. 5B, C). These data suggest a biological scenario and rationale in which the developing mouse tumor secretes NGF into the circulation, where it circulates in the blood to the salivary glands and binds to NGF receptors expressed by salivary acinar cells, activating a signaling pathway that leads to the upregulation of Egr-1 mRNA and protein levels. It should be noted that melanoma cells are derived from melanocytes, which migrate from the neural crest during embryonic development. NGF can stimulate the proliferation and metastasis of melanoma cells [31]. On the other hand, NGF and its receptor (TrkA IR and TrkC IR) have been found in the salivary gland [32], [33]. Therefore, it is reasonable to propose that NGF secreted by melanoma tumor was transferred through blood and bound to its cognate receptors in the salivary gland, ultimately resulting in the stimulation of multiple TFs expression including Egr-1 (Fig. 6).


Systemic disease-induced salivary biomarker profiles in mouse models of melanoma and non-small cell lung cancer.

Gao K, Zhou H, Zhang L, Lee JW, Zhou Q, Hu S, Wolinsky LE, Farrell J, Eibl G, Wong DT - PLoS ONE (2009)

The working model: The relationship between the salivary transcriptome and the remote tumor.Mediators such as NGF secreted by remote tumors are transferred to salivary gland through blood to stimulate TFs expression and alter salivary mRNA profile.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691577&req=5

pone-0005875-g006: The working model: The relationship between the salivary transcriptome and the remote tumor.Mediators such as NGF secreted by remote tumors are transferred to salivary gland through blood to stimulate TFs expression and alter salivary mRNA profile.
Mentions: Since the induction of TFs expression in the salivary glands occurred in mice with a distal tumor, we further hypothesized there are tumor-specific mediators that can effect the altered TG expression in the salivary glands. It is well-known that tumors ectopically express mediators that have systemic effects on distal organs and facilitate metastasis of cancer cells [26], [27]. Melanomas are known to ectopically express TGF-beta [28] while lung tumors ectopically express gonadotropins and other hormones [29], [30]. We investigated if one such signaling pathway can related to one of the identified TFs that can be responsible for induction or suppression of the salivary transcriptome in the mouse melanoma model. Indeed, NGF is known to stimulate expression of the TF Egr-1 through a well-studied signaling pathway (Fig. 5A). Using an NGF ELISA assay, we observed that the concentration of NGF in melanoma tissue and serum is significantly higher than in counterpart control tissues (Fig. 5B, C). These data suggest a biological scenario and rationale in which the developing mouse tumor secretes NGF into the circulation, where it circulates in the blood to the salivary glands and binds to NGF receptors expressed by salivary acinar cells, activating a signaling pathway that leads to the upregulation of Egr-1 mRNA and protein levels. It should be noted that melanoma cells are derived from melanocytes, which migrate from the neural crest during embryonic development. NGF can stimulate the proliferation and metastasis of melanoma cells [31]. On the other hand, NGF and its receptor (TrkA IR and TrkC IR) have been found in the salivary gland [32], [33]. Therefore, it is reasonable to propose that NGF secreted by melanoma tumor was transferred through blood and bound to its cognate receptors in the salivary gland, ultimately resulting in the stimulation of multiple TFs expression including Egr-1 (Fig. 6).

Bottom Line: Saliva (oral fluids) is an emerging biofluid poised for detection of clinical diseases.Taken together, our data support the conclusion that upon systemic disease development, significant changes can occur in the salivary biomarker profile.Although the origins of the disease-induced salivary biomarkers may be both systemic and local, stimulation of salivary gland by mediators released from remote tumors plays an important role in regulating the salivary surrogate biomarker profiles.

View Article: PubMed Central - PubMed

Affiliation: School of Dentistry & Dental Research Institute, University of California Los Angeles, Los Angeles, CA, USA.

ABSTRACT

Background: Saliva (oral fluids) is an emerging biofluid poised for detection of clinical diseases. Although the rationale for oral diseases applications (e.g. oral cancer) is intuitive, the rationale and relationship between systemic diseases and saliva biomarkers are unclear.

Methodology/principal findings: In this study, we used mouse models of melanoma and non-small cell lung cancer and compared the transcriptome biomarker profiles of tumor-bearing mice to those of control mice. Microarray analysis showed that salivary transcriptomes were significantly altered in tumor-bearing mice vs. controls. Significant overlapping among transcriptomes of mouse tumors, serum, salivary glands and saliva suggests that salivary biomarkers have multiple origins. Furthermore, we identified that the expression of two groups of significantly altered transcription factors (TFs) Runx1, Mlxipl, Trim30 and Egr1, Tbx1, Nr1d1 in salivary gland tissue of melanoma-bearing mice can potentially be responsible for 82.6% of the up-regulated gene expression and 62.5% of the down-regulated gene expression, respectively, in the saliva of melanoma-bearing mice. We also showed that the ectopic production of nerve growth factor (NGF) in the melanoma tumor tissue as a tumor-released mediator can induce expression of the TF Egr-1 in the salivary gland.

Conclusions: Taken together, our data support the conclusion that upon systemic disease development, significant changes can occur in the salivary biomarker profile. Although the origins of the disease-induced salivary biomarkers may be both systemic and local, stimulation of salivary gland by mediators released from remote tumors plays an important role in regulating the salivary surrogate biomarker profiles.

Show MeSH
Related in: MedlinePlus