Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse

Kahlert, Christoph; Weber, H.P.; Mogler, Carolin; Bergmann, Frank; Schirmacher, Peter; Kenngott, Hannes; Matterne, Uwe; Mollberg, Nathan M.; Rahbari, Nuh N.; Hinz, Ulf; Koch, Moritz; Aigner, Maximilian; Weitz, Jürgen

doi:10.1038/sj.bjc.6605136

Cited by 95 publications

(99 citation statements)

References 23 publications

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“…Over the last decade, alterations in ALCAM expression have been described in several other malignancies including bladder (6), colorectal (7), esophageal squamous cell (8), pancreatic (9), oral squamous cell (10) and ovarian cancer (11), neuroblastoma (12), prostate (13) and breast cancer (14,15). These data suggest that ALCAM expression is increased in some tumors and downregulated in others.…”

Section: Introductionmentioning

confidence: 68%

“…These data suggest that ALCAM expression is increased in some tumors and downregulated in others. An association between high ALCAM expression and unfavorable prognosis has been shown for colorectal (7), pancreatic (9) and esophageal squamous cell cancer (8), and neuroblastoma (12). As a membrane protein, ALCAM also represents a potential target for therapy, which has already been successfully targeted by human recombinant single-chain antibody in breast cancer cells (16).…”

Section: Introductionmentioning

confidence: 99%

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Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: A TMA-based immunohistochemical study on 2,197 breast cancer patients

et al. 2014

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Abstract. Activated leukocyte cell adhesion molecule (ALCAM) is a membranous cell adhesion protein that is often expressed in breast cancer. Data on the prognostic impact of ALCAM expression is highly controversial in this cancer. To evaluate the clinical impact of ALCAM expression in a sufficiently large patient cohort, we utilized a tissue microarray (TMA) containing more than 2,100 primary breast cancers with clinical follow-up data by immunohistochemistry. TMA spots containing normal breast epithelium showed moderate to strong membranous ALCAM staining. ALCAM staining was strong in 66.2%, moderate in 10.9%, weak in 11.1% and absent in 11.8% of 1,778 (80.9%) interpretable breast cancer tissue spots. Decreased ALCAM expression was significantly associated with advanced tumor size (p=0.0017), unfavorable tumor grade (p<0.0001), negative ER and PR status (p<0.0001 each) as well as high Ki67 labeling index (p<0.0001). Cancers with ACLAM expression loss had a significantly poorer overall (p<0.0001) and disease-specific survival (p= 0.0088). This association also held true in the subset of nodal positive cancers (p<0.0001). In conclusion, these data demonstrate that ALCAM is generally expressed in normal and cancerous breast epithelium and that a marked reduction of ALCAM expression characterizes a subset of breast cancer patients with adverse tumor characteristics and unfavorable clinical outcome.

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Section: Introductionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: A TMA-based immunohistochemical study on 2,197 breast cancer patients

et al. 2014

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“…Recently, numerous genetic and epigenetic alterations were revealed to occur during the development of pancreatic adenocarcinoma and some molecules were reported to be useful for the prediction of prognosis (Infante et al, 2007;Kahlert et al, 2009;Manuyakorn et al, 2010). These factors leads to the selection of patients who actually need to receive the intensive post-operative therapy based on significant parameters.…”

Section: Introductionmentioning

confidence: 99%

Ep-CAM is a significant prognostic factor in pancreatic cancer patients by suppressing cell activity

et al. 2011

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“…The FOX transcription factors that belong to the other (O) subfamily (FOXO) include four members (FOXO1, 3,4,6) in mammals (8). Overexpression of FOXO proteins inhibits tumor growth in vitro and tumor size in vivo (9).…”

Section: Introductionmentioning

confidence: 99%

“…Cluster of differentiation 166 (CD166) is a cell surface member of the immunoglobulin superfamily (1), which is overexpressed and regarded as a valuable prognostic marker of disease progression and poor survival in several types of epithelial tumors (2)(3)(4). Gene silencing of CD166 decreases the concentration of Bcl-2 and increases the level of apoptosis (PARP, active caspase-7) (5).…”

Section: Introductionmentioning

confidence: 99%

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Wang

et al. 2014

Oncology Reports

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Abstract. Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti-carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOXO compared to the control. Moreover, overexpression of CD166 facilitated FOXO protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOXO protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOXO both in vitro and in vivo. Furthermore, CD166 knockdown-induced anti-carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho-FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients. IntroductionCluster of differentiation 166 (CD166) is a cell surface member of the immunoglobulin superfamily (1), which is overexpressed and regarded as a valuable prognostic marker of disease progression and poor survival in several types of epithelial tumors (2-4). Gene silencing of CD166 decreases the concentration of Bcl-2 and increases the level of apoptosis (PARP, active caspase-7) (5). We previously reported that the activation of anti-apoptotic canonical NF-κB signaling greatly induces CD166 expression in liver cancer cells after serum deprivation (6), suggesting its important roles in regulating apoptosis. Most recently, we revealed that CD166 can exert its anti-apoptotic role by enhancing YAP function, demonstrating that CD166 is an upstream regulator of YAP (7). However, overexpression of YAP cannot completely rescue the increased anti-carcinogenic effects evoked by knockdown of CD166 (7). Thus, the downstream regulation of the CD166 pro-carcinogenic function needs to be further explored.The forkhead box transcription factor superfamily consists of 19 subclasses of FOX genes, FOXA-FOXS (8). The FOX transcription factors that belong to the other (O) subfamily (FOXO) include four memb...

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Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse

Cited by 95 publications

References 23 publications

Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: A TMA-based immunohistochemical study on 2,197 breast cancer patients

Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: A TMA-based immunohistochemical study on 2,197 breast cancer patients

Ep-CAM is a significant prognostic factor in pancreatic cancer patients by suppressing cell activity

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

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