Expression Status of Folate Receptor α Is Significantly Correlated with Prognosis in Non-Small-Cell Lung Cancers

Iwakiri, Shotaro; Sonobe, Makoto; Nagai, Shinjiro; Hirata, Toshiki; Wada, Hiromi; Miyahara, Ryoji

doi:10.1245/s10434-007-9755-3

Cited by 96 publications

(92 citation statements)

References 33 publications

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“…Interestingly, however, a study that evaluated 119 non-small cell lung cancers found high FRa expression to be correlated with a better survival. 12 Nonetheless, the association of FRa expression with outcome should promote further research efforts on the prognostic significance of this marker in larger more heterogeneous colorectal cancer populations.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] Its expression in certain epithelial tumors such as ovarian, breast, endometrial and non-small cell lung carcinoma has been associated with tumor behavior. [9][10][11][12] Importantly, FRa expression is tumor specific, as it is significantly higher in tumor cells than in normal cells. 13 FRa also has a high affinity for folic acid; and the high affinity is maintained when folic acid is conjugated with other molecules.…”

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confidence: 99%

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Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

et al. 2011

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Folate receptor alpha (FRa), encoded by folate receptor 1 (adult) gene, has emerged as a cancer biomarker and potential therapeutic target. In addition, its expression in tumors may offer prognostic information. The aim of this study was to assess the prognostic value of FRa expression and other common molecular markers in resected liver metastases from colorectal cancer. To maximize potential biological differences, we selected two groups of patients with markedly different outcomes as study subjects. Immunohistochemical analysis of FRa expression and other common markers (thymidylate synthase, p53, p27, BCL2, ki67, MLH1, MSH2 and MGMT) on tissue microarrays was carried out on samples from 160 patients; 56 patients survived at least 10 years following liver resection, and 104 died within 2 years of surgery. These markers were evaluated and compared with standard clinical predictors of outcome including a previously validated clinical risk score. Our results showed that in addition to known clinical risk factors, FRa positivity was significantly associated with the early death group (32% compared with 13%; P ¼ 0.03). None of the other common molecular markers were differentially expressed between the two groups. On multivariate analysis, clinical risk score, margin status and FRa expression were independently associated with outcome. Specific multivariate comparisons confirmed that FRa expression was associated with outcome independent of the clinical risk score and margin. These data demonstrate that FRa expression is present in a subset of resected hepatic colorectal cancer metastases, and this marker is independently associated with survival after hepatic resection. The prognostic value of FRa expression and the utility of FRa-targeted therapies in stage-IV colorectal cancer patients deserve further exploration. Modern Pathology (2011) 24, 1221-1228; doi:10.1038/modpathol.2011.82; published online 13 May 2011Keywords: folate receptor 1 (adult); folate-targeted therapy; liver metastasisThe liver is the most common site of metastasis from colorectal carcinoma. Although 20 to 25% of colorectal carcinoma patients present with synchronous liver metastases, another 60% develop such metastases after the diagnosis of the primary tumor. 1,2 Surgical resection is potentially curative for colorectal cancer metastases confined to the liver, with a 5-year survival rate between 30 and 50%. 3 Some patients, however, recur early after resection and have a poor outcome. A clinical risk score developed by Fong et al 1 incorporates five preoperative criteria including nodal status of the primary lesion, disease-free interval, number of hepatic metastases, size of the largest metastasis and preoperative carcinoembryonic antigen (CEA) level. This

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

et al. 2011

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“…1,8,9 Examining only lung adenocarcinomas, one study found FOLR1 (the gene encoding FRA) expression level was higher in well-differentiated compared with poorly differentiated tumors. 10 However, this result has not been confirmed at the protein level by immunohistochemistry. In this study, we initially set out to confirm the FRA protein expression pattern in NSCLC using antibody clone 26B3 that had been previously reported.…”

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confidence: 84%

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Driver

Barrios²,

Ge³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Folate receptor a (FRA) is a glycosylphosphatidylinositol-anchored high-affinity folate receptor that localizes to the apical surface of epithelia when it is expressed in normal tissue. Unlike normal tissues, FRA may localize to the basolateral side in tumors. These features make FRA an attractive drug target, and several FRAtargeted drugs have been developed and are in phases of clinical testing. Folate receptor a protein expression shows intertumoral variability that may correlate with response to therapy and to clinicopathologic parameters. Using immunohistochemistry, a recent study of breast carcinomas found FRA protein expression was associated with triple-negative status and high histologic grade in breast cancer. Although a prior study of lung adenocarcinomas found the expression level of the gene encoding FRA, FOLR1, was significantly increased in low-histologic-grade tumors compared to high-histologic-grade tumors, the relationship between FRA protein expression and histologic grade has not been reported for lung adenocarcinomas.Objective.-To investigate the relationship between FRA protein expression level and clinicopathologic parameters in lung adenocarcinomas, including histologic grade, by performing immunohistochemistry for FRA on a cohort of non-small cell lung carcinomas.Design.-High-density tissue microarrays constructed from 188 non-small cell lung carcinomas and used in prior studies were immunostained with FRA-specific antibody clone 26B3. Folate receptor a membranous staining intensity was given a semiquantitative score from 0 to 3þ for triplicate cores of tumor and averaged for each tumor. An average semiquantitative score from 0 to 1.4 was considered low expression, and an average semiquantitative score greater than 1.4 was considered high expression. Conclusions.-Folate receptor a protein was expressed in the majority of lung adenocarcinomas and a minority of lung squamous cell carcinomas. Folate receptor a protein expression correlated with histologic grade for lung adenocarcinomas, and the greatest difference was observed between grade 1 and grade 3. Our results indicate that poorly differentiated adenocarcinomas or focuses of poor differentiation in a heterogeneous tumor may lack FRA protein expression and be more likely to be resistant to FRA-targeting drugs.

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“…TM4SF4 and CRYM genes were reported as tumor markers in lung cancer (17)(18)(19). FOLR1 gene was reported to be overexpressed in lung adenocarcinoma (20,21) and has critical involvement in drug resistance (22). METTL4 gene is known to be related to invasiveness and survival in lung cancer (23), and GUCY1B3 gene was reported to be involved in osteoclast signaling pathway (24).…”

Section: Validation Of Bone-preferentially Expressed Genesmentioning

confidence: 99%

Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice

et al. 2012

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Abstract. Lung cancer is commonly associated with multiorgan metastasis, and the bone is a frequent metastatic site for lung cancer. However, the molecular mechanism of organspecific metastasis remains poorly understood. To elucidate this issue, we analyzed in this study genome-wide gene expression profiles of 15 metastatic lesions from three organs (bone, lung and liver) in a mouse model with multi-organ metastasis properties of human non-small cell lung cancer cells (ACC-LC319/ bone2), using a combination of laser-microbeam microdissection and DNA microarrays. We identified 299 genes that could potentially be involved in the organ-selective nature of lung cancer metastasis. Among them, 77 were bone-specifically expressed elements, including genes involved in cell adhesion, cytoskeleton/cell motility, extracellular matrix remodeling and cell-cell signaling as well as genes already known to be involved in the bone metastasis of breast cancers. Quantitative RT-PCR confirmed the specific upregulation of eight genes in bone metastasis tumors, suggesting that these genes may be involved in bone metastasis. Our findings should be helpful for a better understanding of the molecular aspects of the metastatic process in different organs, and could lead to molecular target-based anticancer drugs and prevention of metastasis, especially bone metastasis.

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Expression Status of Folate Receptor α Is Significantly Correlated with Prognosis in Non-Small-Cell Lung Cancers

Abstract: Higher levels of FOLR1 appear to be associated with better prognoses for patients with lung adenocarcinomas.

Cited by 96 publications

References 33 publications

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice

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