Expression Profiles Provide Insights into Early Malignant Potential and Skeletal Abnormalities in Multiple Endocrine Neoplasia Type 2B Syndrome Tumors

Jain, Sanjay; Watson, Mark A.; DeBenedetti, Mary K.; Hiraki, Yuji; Moley, Jeffrey F.; Milbrandt, Jeffrey

doi:10.1158/0008-5472.can-03-3801

Cited by 65 publications

(69 citation statements)

References 37 publications

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“…In addition, expression analysis of tumors from MEN2A and MEN2B patients was performed (Jain et al 2004). Although, we identified a much larger spectrum of differentially expressed genes, data from the present approach are generally consistent with these studies, indicating that genes involved in the process of cell growth and epithelial to mesenchymal transition are characteristic for MEN2A and MEN2B tumors respectively.…”

Section: Dysregulation Of Host Antitumor Response Mechanisms During Rsupporting

confidence: 80%

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

Engelmann¹,

Koczan²,

Ricken³

et al. 2009

Endocrine-Related Cancer

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Activating mutations in the Ret proto-oncogene are responsible for occurrence of multiple endocrine neoplasia (MEN) type 2A and 2B, and familial medullary thyroid carcinoma (FMTC). A striking genotype-phenotype correlation between the mutated RET codon and clinical manifestation implies that tumorigenesis is conditioned by the type of mutation. We investigated gene expression profiles between and within distinct MEN2 subtypes through whole-genome microarray analysis in tumors induced by NIH-3T3 cells transformed with defined RET-MEN2A (C609Y, C634R), MEN2B, (A883F, M918T), and FMTC (Y791F) mutations. Expression profiling identified a statistically significant modification of 1494 genes, 628 down-and 866 upregulated in MEN2B compared with MEN2A/FMTC tumors. By contrast, no obvious alterations were observed among individual MEN2B and MEN2A type mutations, or between MEN2A and FMTC. Functional clustering of differential genes revealed RET-MEN2B specific upregulation of genes associated with novel growth and survival pathways. Intriguingly, RET-MEN2A/FMTC-specific tumors were characterized by a considerable number of genes involved in the host antitumor immune response via stimulation of natural killer/T-cell proliferation, migration, and cytotoxicity, which were completely absent in RET-MEN2B related cancers. QPCR on tumors versus cultured NIH-RET cell lines demonstrated that they are largely attributed to the host innate immune system, whereas expression of CX3CL1 involved in leukocyte recruitment is exclusively RET-MEN2A/FMTC tumor cell dependent. In correlation, massive inflammatory infiltrates were apparent only in tumors carrying MEN type 2A/FMTC mutations, suggesting that RET-MEN2B receptors specifically counteract immune infiltration by preventing chemokine expression, which may contribute to the different clinical outcome of both subtypes.

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Section: Dysregulation Of Host Antitumor Response Mechanisms During Rsupporting

confidence: 80%

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

Engelmann¹,

Koczan²,

Ricken³

et al. 2009

Endocrine-Related Cancer

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“…Additionally, CEA and other CEACAMs were previously reported to be the MTC-related gene. CEACAM6 and CEACAM7 are upregulated in patients with MEN2B-MTC, which has similar gene expression profiles to the human MTC cell line TT, bearing the RET 634 mutation (1,3,4,10). In support of this, our screening data indicated that TT cells expressed several CEACAMs, including CEACAM6, CEACAM7, and an MTCspecific CEACAM member CEACAM4 (Table 2).…”

Section: Reverse Transcription Polymerase Chain Reaction (Rt-pcr)supporting

confidence: 71%

Carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) is specifically expressed in medullary thyroid carcinoma cells

et al. 2014

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Carcinoembryonic antigen (CEA), an oncofetal cell surface glycoprotein, has been widely used as a human tumor marker due to its high expression in tumors and secretion to serum. It belongs to the immunoglobulin superfamily named CEA-related cell adhesion molecule (CEACAM) family. Members of this family are detected in various cancers and have been shown to be involved in cancer growth and invasion. In this study, we examined the mRNA expression profiles of CEACAM family members including CEACAM1, CEACAM3, CEACAM4, CEACAM5 (CEA), CEACAM6, CEACAM7, and CEACAM8 in various tumor cell lines. Our screening data indicated that the mRNA expression patterns of CEACAMs in TT cells, which are derived from medullary thyroid carcinoma (MTC), were distinct from other tumor cell lines. Additionally, CEACAM4 was only expressed in TT cells, in which two novel splice variants of CEACAM4 were expressed. These findings suggested that production of CEA and CEA-related molecules in MTC may be distinct from other tumor-based production of those molecules and that the specific expression of CEACAM4 would make possible to differentiate between MTC and other CEA-producing tumors.Carcinoembryonic antigen (CEA) is the product of the CEA-related cell adhesion molecule 5 (CEACAM5) gene and is produced in a high percentage of human tumors, including 90% of gastrointestinal cancers, 70% of lung cancers, and 50% of breast cancers (22). Because of its high secretion into the serum, CEA has been widely used as a serum tumor marker; currently, CEA analysis is used to monitor the progression of several types of cancer following surgery. CEA belongs to the CEACAM subfamily of the immunoglobulin (Ig) superfamily. The members of this family have been identified as CEA crossreacting antigens and have been found in tumor sites with elevated CEA-like activity. Moreover, CEACAMs are also produced in various tumors, and recent studies have suggested that multivariable analysis of CEACAMs may improve the clinical utility of CEA as a tumor maker (6, 24). For example, Simeone et al. reported that CEACAM1 may be used to enhance the efficacy of other known pancreatic tumor markers and may have better sensitivity and specificity than CA19-9 and CEA for the detection of pancreatic carcinoma (20). In addition, using those biomarkers in combination with CEACAM1 may represent a novel method for the diagnosis of early-stage pancreatic carcinoma. In this study, we analyzed the mRNA expression profiles of CEACAM family members in colonic, gastric, pancreatic, lung, breast, and thyroid cancer cell lines. Our data demonstrated that a medullary thyroid carcinoma (MTC)-derived cell line exhibited unique CEACAM expression patterns, with CEACAM4 specifically expressed in TT cells.

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“…Because transcriptome profiles of a pure, normal population of C-cells are not available, we focused our attention on a previously analyzed set of profiles from metastatic medullary carcinomas (MTC) in MEN2B patients (Jain et al, 2004;Ippolito et al, 2005), as these tumors derive from C-cells. As a comparison, we used a set of profiles obtained from primary papillary thyroid carcinoma of follicular subtype (PTCF; International Genomics Consortium, expO).…”

Section: Isl1 Is Expressed In Medullary Thyroid Cancermentioning

confidence: 99%

“…The first data set (Jain et al, 2004;Ippolito et al, 2005) included samples from 11 medullary thyroid carcinomas (MTC, primary and metastatic) from MEN2B patients, which have been hybridized on Affymetrix GeneChip HG-U95Av2 arrays. The second data set (International Genomics Consortium, expO) included samples from 9 papillary thyroid carcinomas (follicular variant; PTCF), which have been hybridized on Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays.…”

Section: Microarray Data Analysismentioning

confidence: 99%

Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia

Westerlund¹,

Andersson²,

Carlsson³

et al. 2008

Developmental Dynamics

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The LIM homeodomain transcription factor Isl1 was investigated in mouse thyroid organogenesis. All progenitor cells of the midline thyroid diverticulum and lateral primordia (ultimobranchial bodies) expressed Isl1. This pattern persisted until the growing anlagen fused at embryonic day (E) 13.5. In Isl1 null mutants thyroid progenitors expressing Nkx2.1 and Pax8 were readily specified in the anterior endoderm but the size of the thyroid rudiment was reduced. In late development, only immature C-cells expressed Isl1. In the adult gland the number of Isl1؉ cells was small compared with cells expressing calcitonin. Analysis of microarray profiles indicated a higher level of Isl1 expression in medullary thyroid carcinomas than in tumors derived from follicular cells. Together, these findings suggest that Isl1 may be a novel regulator of thyroid development before terminal differentiation of the endocrine cell types. Isl1 is an embryonic C-cell precursor marker that may be relevant also in cancer developed from the mature C-cell. Developmental Dynamics 237:3820 -3829, 2008.

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Expression Profiles Provide Insights into Early Malignant Potential and Skeletal Abnormalities in Multiple Endocrine Neoplasia Type 2B Syndrome Tumors

Cited by 65 publications

References 37 publications

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

Carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) is specifically expressed in medullary thyroid carcinoma cells

Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia

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