CA : A Cancer Journal for Clinicians

Background Determining the stage of non–small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor. Methods We prospectively compared the ability of a standard approach to staging (computed tomography [CT], ultrasonography, bone scanning, and, when indicated, needle biopsies) and one involving PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable non–small-cell lung cancer. The presence of mediastinal metastatic disease was confirmed histopathologically. Distant metastases that were detected by PET were further evaluated by standard imaging tests and biopsies. Patients were followed postoperatively for six months by standard methods to detect occult metastases. Logistic-regression analysis was used to evaluate the ability of PET and CT to identify malignant mediastinal lymph nodes. Results The sensitivity and sp...

Preoperative staging of non-small-cell lung cancer with positron-emission tomography.

https://www.gastrojournal.org/article/S0016-5085(15)01005-7/pdf

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

Two sides of the same coin

Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell-cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.

https://www.mdpi.com/2072-6694/9/12/171/pdf

Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis.

We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer. TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity. These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease.

/pdf/tpx2-is-a-novel-prognostic-marker-for-the-growth-and-3ye87q9ir6.pdf

TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer

Long noncoding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules, which were involved in a broad range of biological processes and complex diseases. Research on lncRNAs may shed light on tumorigenesis and progression of colorectal cancer (CRC). The purpose of the present study was to identify lncRNAs correlated with CRC and then investigate their potential functions. We selected 92 patients for this prospective study and then collected the tumor samples and clinical records. First, the global lncRNA expression profiles in tumor and adjacent normal tissues of patients with non-metastatic CRC and patients with metastatic CRC were measured by microarray assay. Then, a noteworthy lncRNAs RP11-462C24.1 whose function was previously unknown was explored in detail on the aspect of the association of its expression level and clinicopathological features of CRC and patients’ survival. We found that RP11-462C24.1 expression level was lower in cancer tissues compared with adjacent normal samples (P < 0.001). Furthermore, its expression level was lower in CRC patients with metastasis than those without metastasis (P = 0.049). That is, RP11-462C24.1 expression level decreased as the malignant degree of CRC increased. In addition, low expression of RP11-462C24.1 significantly correlated with more distant metastasis (P = 0.011). The areas under ROC curves were 0.78 and 0.65 for RP11-462C24.1, distinguishing CRC from normal tissue and distinguishing CRC without metastasis from CRC with metastasis, respectively. Multivariate analysis identified that RP11-462C24.1 was an independent predictor for patients prognosis (P = 0.005). Furthermore, Kaplan–Meier analysis showed that patients with low expression of RP11-462C24.1 had a poor disease-free survival (P < 0.001). This is the first study that correlates RP11-462C24.1 expression profile with malignancy grade in human CRC. Our results showed that RP11-462C24.1 could be a potential novel prognostic marker for CRC, and thus, provided a new strategy for CRC diagnosis. Meanwhile, our findings indicated the potential roles of RP11-462C24.1 in tumorigenesis and progression of CRC, which gave a clue for future studies.

/pdf/low-expression-of-novel-lncrna-rp11-462c24-1-suggests-a-u7kekdktfs.pdf

Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer.

Forkhead box protein C2 (FOXC2) plays a vital role in carcinogenesis; however, its significance and prognostic value in colon cancer remain unclear. In this study, FOXC2 expression was analyzed in a tissue microarray (TMA) containing 185 samples of primary colon cancer tumor samples and in human colon cancer cell lines. The effect of FOXC2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. FOXC2 was overexpressed in human colon cancer cells and tissues, and correlated with colon cancer progression and patient survival. Functional study demonstrated that FOXC2 promoted cell growth, cell migration, and tumor formation in nude mice, whereas knockdown of FOXC2 by short hairpin RNA (shRNAs) significantly suppressed cell growth, cell migration and tumor formation. Further study found that FOXC2 enhanced AKT activity with subsequent GSK-3β phosphorylation and Snail stabilization, and then induced epithelial-mesenchymal transition (EMT) and promoted tumor invasion and metastasis. Collectively, FOXC2 promotes colon cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colon cancer.

Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition

Objective 
To compare the long-term survival of colorectal cancer (CRC) in young patients with elderly ones.


Methods 
Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 69,835 patients with non-metastatic colorectal cancer diagnosed between January 1, 1988 and December 31, 2003 treated with surgery. Patients were divided into young (40 years and under) and elderly groups (over 40 years of age). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.


Results 
Young patients showed significantly higher pathological grading (p<0.001), more cases of mucinous and signet-ring histological type (p<0.001), later AJCC stage (p<0.001), more lymph nodes (≥12 nodes) dissected (p<0.001) and higher metastatic lymph node ratio (p<0.001). The 5-year colorectal cancer specific survival rates were 78.6% in young group and 75.3% in elderly group, which had significant difference in both univariate and multivariate analysis (P<0.001). Further analysis showed this significant difference only existed in stage II and III patients.


Conclusions 
Compared with elderly patients, young patients with colorectal cancer treated with surgery appear to have unique characteristics and a higher cancer specific survival rate although they presented with higher proportions of unfavorable biological behavior as well as advanced stage disease.

/pdf/better-long-term-survival-in-young-patients-with-non-3q9xdi2tjf.pdf

Better long-term survival in young patients with non-metastatic colorectal cancer after surgery, an analysis of 69,835 patients in SEER database.

The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.

/pdf/foxm1-promotes-lung-adenocarcinoma-invasion-and-metastasis-1q8kfkcwva.pdf

Dawei Li

Papers

TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer

Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer.

Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition

Better long-term survival in young patients with non-metastatic colorectal cancer after surgery, an analysis of 69,835 patients in SEER database.

FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL.