Abstract 1149: The expression of Ki-67, but not IGF1R, predicts a poor disease-free survival in patients with adenocarcinoma of the lung

Oka, Soichi; Uramoto, Hidetaka; Chikaishi, Yasuhiro; Nakagawa, Makoto; Shimokawa, Hidehiko; Takenaka, Masaru; Shigematu, Yoshiki; Saito, Tomoko; Hanagiri, Takeshi; Tanaka, Fumihiro

doi:10.1158/1538-7445.am2012-1149

Cited by 37 publications

(48 citation statements)

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“…S3). Another study corroborated these findings by showing that patient survival was decreased from 84% to 50% for patients with tumors expressing CD146 [28]. For these reasons, CD146 has become an attractive biomarker for predicting patient survival, stratification of cancer patients, and the development of CD146-targeted therapies.…”

Section: Discussionmentioning

confidence: 78%

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Sun

England

Hernandez

et al. 2016

Eur J Nucl Med Mol Imaging

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Purpose Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. In this study, we describe the generation of a 64Cu-labeled CD146-specific antibody for quantitative immunoPET imaging of CD146 expression in six lung cancer models. Methods The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative Western blot studies. The biodistribution and tumor uptake of 64Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of 64Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146. Results Flow cytometry and Western blot studies showed similar findings with H460 and H23 cells highly expressing CD146. Small differences in CD146 expression levels were found between A549, H4006, H522, and H358 cells. Tumor uptake of 64Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h post-injection (n=4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h post-injection; n=4), while H4006, A549 and H358 exhibited similar uptake of 64Cu-NOTA-YY146. A positive correlation was found between tumor uptake of 64Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r2=0.98, p<0.01). Ex vivo biodistribution corroborated the accuracy of PET data. Conclusions The strong correlation between tumor uptake of 64Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.

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Section: Discussionmentioning

confidence: 78%

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Sun

England

Hernandez

et al. 2016

Eur J Nucl Med Mol Imaging

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“…Additionally, we revealed the prognostic relevance of a LEF1/TCF4 signature in primary lung adenocarcinomas in a microarray dataset of primary lung adenocarcinomas. Independently, we demonstrated that Ki67 expression in the metastatic tissues, a recently established marker in early-stage primary lung cancer tissue [8], still has prognostic value in this late stage of the disease. Interestingly, there was a trend in nuclear LEF1 expression to correlate with high proliferation index Ki67.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, some of the histological markers in primary lung adenocarcinomas have prognostic impact. TTF1-negativity as well as a high proliferation index Ki67 are associated with poor overall survival in early-stage disease [5–8]. …”

Section: Introductionmentioning

confidence: 99%

Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear β-catenin in cerebral metastasis of lung adenocarcinomas

Bleckmann

Siam

Klemm

et al. 2012

Clin Exp Metastasis

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An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/β-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, β-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear β-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear β-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/β-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not β-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of β-catenin in this setting.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-012-9552-7) contains supplementary material, which is available to authorized users.

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“…Previous reports showed that Ki-67 expression was associated with tumor progression and patient survival in various human cancers including colorectal cancer (30)(31)(32). Recently, Egr-1 was found to promote tumor cell proliferation in gastric cancer cells (33).…”

Section: Egr-1 -----------------------------------Parametersmentioning

confidence: 98%

Expression of early growth response-1 in colorectal cancer and its relation to tumor cell proliferation and apoptosis

et al. 2013

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Early growth response-1 (Egr-1) is implicated in the regulation of cell growth, proliferation, differentiation and apoptosis. Egr-1 is considered tobe either a tumor-suppressor or tumor-promoter, depending on the cell type and environment. The aim of the present study was to evaluate the expression of Egr-1 in colorectal cancer and its correlation with tumor cell proliferation, apoptosis and clinicopathological features. The expression of Egr-1 in colorectal cancer tissues was investigated by reverse transcription-polymerase chain reaction (RT-PCR), western blotting and immunohistochemistry. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and cellular proliferative activity was evaluated by immunohistochemical staining with the Ki-67 antibody. Egr-1 expression was significantly elevated in colorectal cancer tissues, when compared to that in the paired normal mucosa at the mRNA and protein levels. In addition, Egr-1 expression was significantly increased in the metastatic lymph node tissues, when compared to that in the non‑metastatic lymph node tissues at the protein level. The mean Ki-67 labeling index (KI) and apoptotic index (AI) values for 158 tumors were 53.6±15.4 and 9.0±1.0, respectively. Higher KI values were significantly associated with distant metastasis. Lower AI values were significantly associated with lymph node metastasis. However, KI or AI values were not associated with patient survival. The mean KI value of Egr-1-positive tumors was significantly higher than that of Egr-1-negative tumors. However, there was no significant difference between Egr-1 expression and AI value. Positive expression of Egr-1 was significantly associated with age, lymphovascular invasion, lymph node and distant metastasis, tumor stage and poor survival. These results indicate that Egr-1 may be associated with colorectal cancer progression via tumor cell proliferation.

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Abstract 1149: The expression of Ki-67, but not IGF1R, predicts a poor disease-free survival in patients with adenocarcinoma of the lung

Cited by 37 publications

References 0 publications

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear β-catenin in cerebral metastasis of lung adenocarcinomas

Expression of early growth response-1 in colorectal cancer and its relation to tumor cell proliferation and apoptosis

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