Microtubule-Associated Protein-2: A New Sensitive and Specific Marker for Pulmonary Carcinoid Tumor and Small Cell Carcinoma

Liu, Yulin; Sturgis, Charles D.; Grzybicki, Dana M.; Jasnosz, Katherine M.; Olson, Peter; Tong, Ming; Dabbs, David D.; Raab, Stephen S.; Silverman, Jan F.

doi:10.1038/modpathol.3880406

Cited by 43 publications

(30 citation statements)

References 22 publications

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“…Levels of MAP2 are reported to be increased in brain tumors, melanocytic tumors, pulmonary carcinoid tumors and small cell lung cancers, all of which are related to the nervous and neuroendocrine systems. [35][36][37][38] Expression of tau was observed in tumors including astrocytomas, oligodendrogliomas, chondrosarcomas and gastrointestinal stromal tumors, [39][40][41] and tau phosphorylation is associated with anti-cancer drug sensitivity and drug-induced apoptosis. [42][43][44][45] We and other investigators found that expression of the CKAP2 gene is also upregulated in some human tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification of a mouse cytoskeleton‐associated protein, CKAP2, with microtubule‐stabilizing properties

Jin¹,

Murakumo²,

Ueno³

et al. 2004

Cancer Science

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Microtubule dynamics is an important factor in cell proliferation and one of the main targets of cancer chemotherapy. Since microtubule-associated proteins (MAPs) are known to influence microtubule stability, study of MAPs may contribute both to knowledge of cancer cell biology and to the production of new anti-cancer drugs. In this study, we identified a new mouse gene which is a homolog of human cytoskeleton-associated protein, CKAP2 gene, by differential display analysis. The level of expression of mouse CKAP2 (mCKAP2) was significantly higher in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A or MEN2B mutation than in parental NIH3T3 cells. Immunocytochemical analysis showed that mCKAP2 protein is localized in cytoplasm with a fibrillar appearance, and is co-localized with microtubules throughout the cell cycle. Furthermore, overexpression of mCKAP2 in cells appeared to stabilize microtubules against treatment with nocodazole, a microtubule-depolymerizing agent. In addition, levels of human CKAP2 were increased in some human tumor cell lines examined. These findings suggest that CKAP2 is a new MAP with microtubule-stabilizing properties and may represent a new molecular target for cancer chemotherapy. (Cancer Sci 2004; 95: 815-821) ell proliferation is closely associated with cytoskeleton organizing proteins, which play crucial roles in maintenance of cell structure, as well as mitotic progression. Of the three main filamentous components, microtubules, actin filaments and intermediate filaments, microtubules are known to play roles in intracellular organelle transport, cell division, and maintenance of cell morphogenesis.1-3) Microtubules are composed of α-and β-tubulin proteins, and since their polymerization and depolymerization are essential for cell proliferation, various anti-cancer drugs have been produced to target microtubule dynamics and thereby inhibit mitotic progression. Some of these drugs inhibit microtubule polymerization, while others inhibit microtubule depolymerization. [3][4][5] Microtubule dynamics is regulated by accessory proteins called microtubule-associated proteins (MAPs).6, 7) Many proteins have been identified as MAPs, and can be generally classified into two categories, microtubule-stabilizing proteins and microtubule-destabilizing proteins. The former include tau, MAP2 and MAP4, while the latter include Op18/stathmin and heat shock protein HSP90. [8][9][10][11][12][13] Thus, characterization of the effects of MAPs on microtubule dynamics is necessary for investigation of the mechanisms of tumorigenesis and production of new anti-cancer drugs.Neoplastic transformation of cells is triggered by genetic alterations which cause extraordinary cell growth and proliferation. A mutation in an oncogene can alter the function of its product, and the oncogenic signaling from the mutated protein can result in various neoplastic properties.14, 15) RET proto-oncogene encodes a transmembrane receptor with a tyrosine kinase domain which is expressed in cells derived ...

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Section: Discussionmentioning

confidence: 99%

Identification of a mouse cytoskeleton‐associated protein, CKAP2, with microtubule‐stabilizing properties

Jin¹,

Murakumo²,

Ueno³

et al. 2004

Cancer Science

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“…Currently, anti-NSE antibody is used as a tool for primary screening (4,33). The reported sensitivity of CGA and SYN for small cell lung carcinoma varies from 0.0 to 1.0 (4,7,8,31,32,34). Because these markers are components of neurosecretory granules (1) and synaptic vesicles (35), respectively, their detectability is directly linked to the numbers of subcellular organelles (2).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, anti-neuron-specific enolase (NSE) antibody is highly reactive for neuroendocrine tumors, but its specificity is poor because of cross-reactivity (6). Recent studies have revealed that new makers such as CD56 and microtubulesassociated protein-2 provide a higher sensitivity for small cell lung carcinoma with a relatively lower frequency of heterogeneous staining (7,8).…”

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confidence: 99%

Histidine Decarboxylase Expression as a New Sensitive and Specific Marker for Small Cell Lung Carcinoma

et al. 2003

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Histidine decarboxylase is one of the enzymes of the amine precursor uptake and decarboxylation system and is known to be distributed in mast cells and enterochromaffin-like cells. With the hypothesis that histidine decarboxylase expression is a marker for neuroendocrine differentiation, we studied the immunoreactivity of histidine decarboxylase in neuroendocrine cells and tumors of the thyroid gland, adrenal medulla, lung, and gastrointestinal tract. Formalin-fixed paraffin sections were subjected to immunohistochemistry using antihistidine decarboxylase antibody, and the sensitivity and specificity were compared with those of conventional neuroendocrine markers (CD56, chromogranin A, synaptophysin, and neuron-specific enolase). Enterochromaffin or enterochromaffinlike cells, adrenal chromaffin cells, and thyroid C-cells were positive for histidine decarboxylase, and related tumors (carcinoid tumor, pheochromocytoma, medullary carcinoma) showed a high percentage of positive staining. Furthermore, we used the antibody to distinguish small cell lung carcinoma from non-neuroendocrine lung carcinoma and also to detect neuroendocrine differentiation in large-cell neuroendocrine carcinoma and gastrointestinal small-cell carcinoma. The anti-histidine decarboxylase antibody stained most small cell lung carcinoma (18 of 23, sensitivity 0.78), and was rarely reactive with non-neuroendocrine lung tumors (2 of 44; specificity, 0.95). These values were close to those obtained from CD56 staining (sensitivity/ specificity, 0.87/0.98). Histidine decarboxylase was also positive for 6 of 12 large cell neuroendocrine carcinomas and 4 of 7 gastrointestinal small cell carcinomas. In conclusion, we demonstrated that histidine decarboxylase is useful to distinguish between small cell lung carcinoma and nonneuroendocrine carcinoma and to demonstrate neuroendocrine differentiation.

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“…Variable MAP2 immunoreactivity is found in most pulmonary neuroendocrine carcinomas and in some non -small-cell carcinomas (13), whereas Merkel cell carcinomas show diffuse to focal MAP2 expression. MAP2 is thought to be a valuable ancillary marker in skin tumors suspicious of neuroendocrine origin (14).…”

Section: Mapsmentioning

confidence: 99%

Microtubule-Associated Proteins as Targets in Cancer Chemotherapy

Bhat

Setaluri

2007

Clinical Cancer Research

179

142

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Natural and synthetic compounds that disrupt microtubule dynamics are among the most successful and widely used cancer chemotherapeutic agents. However, lack of reliable markers that predict sensitivity of cancers to these agents and development of resistance remain vexing issues. There is accumulating evidence that a family of cellular proteins that are associated with and alter the dynamics of microtubules can determine sensitivity of cancer cells to microtubuletargeting agents and play a role in tumor cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products of oncogenes, tumor suppressors, and apoptosis regulators, suggesting that alteration of microtubule dynamics may be one of the critical events in tumorigenesis and tumor progression. The objective of this review is to integrate the knowledge on these seemingly unrelated proteins that share a common function and examine their relevance to microtubule-targeting therapies and highlight MAPs-tubulin-drug interactions as a novel avenue for new drug discovery. Based on the available evidence, we propose that rational microtubule-targeting cancer therapeutic approaches should ideally include proteomic profiling of tumor MAPs before administration of microtubule-stabilizing/destabilizing agents preferentially in combination with agents that modulate the expression of relevant MAPs.

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Microtubule-Associated Protein-2: A New Sensitive and Specific Marker for Pulmonary Carcinoid Tumor and Small Cell Carcinoma

Cited by 43 publications

References 22 publications

Identification of a mouse cytoskeleton‐associated protein, CKAP2, with microtubule‐stabilizing properties

Identification of a mouse cytoskeleton‐associated protein, CKAP2, with microtubule‐stabilizing properties

Histidine Decarboxylase Expression as a New Sensitive and Specific Marker for Small Cell Lung Carcinoma

Microtubule-Associated Proteins as Targets in Cancer Chemotherapy

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