Prognostic significance of L1CAM in cervical cancer: A narrative review.

Cervical cancer (CC) is the fourth most common malignancy. The significant prognostic factors are tumor size and lympho-vascular space invasion. Considering that these are nonspecific factors, research has been aimed at finding a specific molecular marker related to a higher incidence of relapse and mortality in patients with CC. Our study investigated the prognostic value of L1 cell adhesion molecule (L1CAM) expression in rare histological subtypes of cervical cancer (adenocarcinomas and adenosquamous cell carcinomas). This is a single-institution retrospective study with 35 patients who underwent radical hysterectomy for early-stage cervical adenocarcinoma or adenosquamous cell carcinoma in 2007 through 2017. Paraffin sections of the tumor were used for L1CAM analysis by immunohistochemistry. L1CAM expression was positive in 15 (42.8%) of the 35 tumors. L1CAM expression did not differ significantly in regard to the stage of disease, tumor size, grading, or lymphovascular space invasion (LVSI) (p = 0.619, p = 0.341, p = 0.445, p = 0.999). Progression-free interval and overall survival did not differ between L1CAM-positive and L1CAM-negative groups (p = 0.704, p = 0.386, respectively). In our study, L1CAM expression is not a negative prognostic factor associated with aggressive tumor behavior, recurrence risk and overall survival.

Background:Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas.Methods:The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated.Results:In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs.Conclusions:The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.

Introduction/BackgroundEndometrial cancer is one the most common female cancers, a better stratification into high- or low-risk is mandatory to identified patients who might benefit of a tailored adjuvant therapy. Recent...

Background Endometrial carcinoma is the most common invasive neoplasm of the female reproductive tract. L1 cell adhesion molecule (L1CAM), Sperm-associated antigen 9 (SPAG9), and P53 have a role in the process of tumorigenesis and progression of several human malignant tumors, however, the role of them in cancer of endometrium is still not clear. Aim The study was performed to evaluate L1CAM, SPAG9, and P53 expression about different clinicopathological parameters in endometrial endometrioid adenocarcinoma. Methods The immunohistochemical study was performed on 50 cases of endometrial lesions including endometrial hyperplasia without atypia (10 cases), endometrial hyperplasia with atypia (10 cases), and endometrial endometrioid carcinoma (30 cases). Immunohistochemical staining techniques were used to evaluate the role of L1CAM, P53, and SPAG9 in endometrial endometrioid adenocarcinoma (EEC) and their relation to different clinicopathological data and patient’s survival followed for 36 months. Results This study declared that both L1CAM and SPAG9 were found to be upregulated in EEC. Their over-expression was related to adverse clinicopathological parameters including high tumor grade, deep myometrial invasion, lymphovascular Invasion (LVI), and advanced tumor stage, while there was no significant relation between their expression and tumor size, cervical affection, and lymph node involvement. A high statistically significant link between L1CAM expression and poor patient survival was detected. Mutant type P53 was significantly related to adverse clinicopathological data as high tumor grade, deep myometrial invasion, lymphovascular space invasion (LVSI), and high tumor stage. There was a positive significant relation between mutant type P53 and high SPAG9. Conclusions The early identification of EEC in asymptomatic high-risk women may benefit from L1CAM and SPAG9 testing in combination with P53 protein. Also, they could be viewed as separate predictive variables in the EEC and might play a crucial part in the EEC’s chemoresistance.

Our study aimed to assess expression of L1 cell adhesion molecule (L1CAM) in early-stage cervical squamous-cell cancer as a prognostic factor. This retrospective, single-institution study included 154 patients who underwent radical hysterectomy for early-stage squamous cell cervical cancer between 2007 and 2017. Tumor samples from 154 patients were available for L1CAM analysis by immunohistochemistry. Among all patients, radical abdominal hysterectomy was performed in 144 cases. L1CAM expression was positive in 24 tumors (15.6%) of the whole group. In relation to the grade of differentiation and the presence of lymphovascular invasion, L1CAM expression did not show an association (p=0.154 and p=0.306, respectively). The disease-free interval and overall survival also did not significantly differ between L1CAM-positive and L1CAM-negative cases (p=0.427 and p=0.240, respectively). For histopathological characteristics, L1CAM-positive cases had a significantly higher median tumor size (p=0.015). Even in the selected group of 115 cases without nodal infiltration, L1CAM status had no effect on the relapse rate during follow-up. Our study did not confirm the results of previous studies showing L1CAM expression to be a negative prognostic factor in cervical cancer. In our study, increased L1CAM expression in early-stage squamous-cell cervical cancer was not associated with adverse prognosis regarding disease recurrence, disease-free survival, nor overall survival. L1CAM expression was correlated only with the size of the tumor.

AimsL1 cell adhesion molecule (L1CAM) has been shown to be correlated with tumour progression, attributed to its possible association with epithelial-mesenchymal transition (EMT), characterised by the expression of vimentin and...

We investigate L1 cell adhesion molecule (L1CAM) expression in estrogen receptor (ER)-positive/human epidermal growth factor receptor (HER2)-negative breast carcinomas. The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B breast carcinomas may be helpful for risk stratification and open opportunities for targeted therapies. 304 cases comprising 152 cases of ER-positive, progesterone receptor (PR)-positive/negative, and HER2-negative recurrent/metastatic breast carcinomas and 152 nonrecurrent controls were included. ER, PR, HER-2, Ki-67 status, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, laterality, age at diagnosis and first distant or local recurrence were recorded. L1CAM positive cases showed increased specificity for recurrence and these patients were significantly younger than L1CAM negative ones. Compared with L1CAM negative recurrent cases, L1CAM positive ones had a noticeably higher Ki-67, tended to be larger and recurred sooner. All L1CAM positive recurrent/metastatic cases were of the luminal B subtype compared with 67.3% of the L1CAM negative cases. L1CAM is highly specific for recurrence in a subset of breast cancer patients and may be associated with more aggressive behavior, particularly in luminal B breast cancers with higher Ki-67 expression. Further investigation about the prognostic value of L1CAM is warranted.

Background. L1CAM (L1 Cell Adhesion Molecule) is a glycoprotein identified as a key mediator of the metastatic process in many different tumor types. It facilitates the detachment of tumor cells from the primary tumor and their entry into the circulation. By promoting cell-cell interactions, it also directly stimulates the colonization of distant organs by circulating tumor cells. The expression and role of L1CAM in B and T cell lymphomas is poorly explored. The aim of this project was to evaluate L1CAM expression in different subtypes of lymphoma and its role as novel therapeutic target. Methods. RNA was extracted with Monarch Total RNA Miniprep Kit and qPCR performed with QuantiFast SYBR Green RT-PCR. For flow cytometry (FACS), cells were stained either with anti-L1CAM antibody or isotype control at a dilution of 1:1000. For immunohistochemistry (IHC) samples were stained for 20 minutes at a dilution of 1:100. For direct killing assay, cells were exposed six days to compounds, followed by MTT assay. Antibody dependent cellular cytotoxicity (ADCC) was performed with ADCC Reporter Bioassay (Promega). Results. L1CAM mRNA expression was assessed in 59 lymphoma cell lines. Whereas expression in most cell lines appeared low, a subgroup of cells displayed high to very high expression of L1CAM. Surface L1CAM expression was confirmed by FACS. L1CAM mRNA and protein expression levels correlated well across the cell lines and revealed that Sezary syndrome (SS) cell lines displayed the highest expression, followed by mantle cell lymphoma (MCL) and activated B cell diffuse large B cell lymphoma (ABC DLBCL) cell lines. By IHC L1CAM expression was assessed on different tissue microarrays covering multiple lymphoma subtypes; L1CAM expression was observed especially in a subset of cutaneous T-cell lymphoma and MCL. The data confirmed the findings in lymphoma cell lines. Anti-L1CAM monoclonal antibody (mAb) and four L1CAM targeting antibody drug conjugates (ADCs) (ADC1, ADC4, ADC5, ADC6), differing for the linker and payload, were tested in L1CAM positive and negative cell lines. mAB did not show any sign of direct antitumoral activity. Among ADCs, highest activity was observed with ADC6 (SG3199 payload), followed by ADC4 (MMAE payload). ADC1 and ADC5 (also containing MMAE as payload) showed limited activity. ADC6 showed the best correlation between killing activity and L1CAM expression levels, indicating a high level of target specific activity. The in vitro activity of ADC4 and ADC6 was validated in an in vivo xenograft using the MCL cell line Z138. Finally, mAb and a bispecific anti-CD3/L1CAM antibody were tested for their ability to induce ADCC. Both induced strong intracellular signaling in the reporter cell line upon co-incubation with L1CAM expressing lymphoma cells, indicative of the induction of killing activity in effector cells. Conclusions. In summary, we have demonstrated the in vitro and in vivo activity of anti-L1CAM antibody-based therapeutic approach as novel treatment for L1CAM positive lymphomas. Citation Format: Filippo Spriano, Giulio Sartori, Luca Aresu, Luciano Cascione, Elisa Civanelli, Afua A. Mensah, Chiara Tarantelli, Stefano Pileri, Flavio Mehli, Gunther Spohn, Francesco Bertoni. L1CAM targeting antibody-based therapy as a novel approach for L1CAM positive lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C112.

BackgroundThe L1 cell adhesion molecule (L1CAM) was originally identified as a neural adhesion molecule involved in axon guidance. In many human epithelial carcinomas L1CAM is overexpressed and thereby augments cell motility, invasion and metastasis formation. L1CAM positive carcinomas are associated with bad prognosis. Recent data point out that L1CAM is regulated in a fashion similar to epithelial-mesenchymal transition (EMT). Previous studies have implied the transcription factors Slug and/or β-catenin in L1CAM transcriptional regulation. However, the regulation of human L1CAM expression at the transcriptional level is not well understood.ResultsTo better understand the molecular basis of L1CAM transcriptional regulation, we carried out a detailed characterization of the human L1CAM promoter. We identified two transcription start sites, the first in front of a non-translated exon 0 (promoter 1) and the other next to the first protein-coding exon 1 (promoter 2). Both sites could be verified in endometrial carcinoma (EC) cell lines and appear to be used in a cell-type specific manner. The two identified promoter regions showed activity in luciferase reporter assays. Chromatin-IP analyses confirmed the in silico predicted E-boxes, binding sites for transcription factors Snail and Slug, as well as Lef-1 sites, which are related to β-catenin-mediated transcriptional regulation, in both promoters. Overexpression of β-catenin exclusively augmented activity of promoter 1 whereas Slug enhanced promoter 1 and 2 activity suggesting that both promoters can be active. Overexpression of β-catenin or Slug could upregulate L1CAM expression in a cell-type specific manner.ConclusionsOur results, for the first time, provide evidence that the L1CAM gene has two functionally active promoter sites that are used in a cell-type specific manner. Slug and β-catenin are involved L1CAM transcriptional regulation. Nevertheless, Slug rather than β-catenin levels are correlated with L1CAM expression in EC cell lines. Our findings suggest that the L1CAM transcriptional regulation is more complex than anticipated and this study provides the basis for a better understanding of L1CAM regulation in non-neuronal/tumor cells.

L1 cell adhesion molecule (L1CAM) has been implicated in the progression and metastasis of numerous cancers. However, the role of L1CAM in oral squamous cell carcinoma (OSCC) is not well characterized. In the present study, the expression of L1CAM was examined in oral tongue squamous cell carcinoma (OTSCC) tissue samples by immunohistochemistry, the clinicopathological significance of L1CAM expression was evaluated by chi-squared test, and the overall survival (OS) rate was analyzed using Kaplan-Meier method according to the expression of L1CAM. In addition, it was aimed to elucidate the biological role of L1CAM and the underlying molecular mechanisms by which L1CAM functions in OSCC cells in relation to epithelial-mesenchymal transition (EMT) and PI3K/AKT/ERK signaling pathways. Thus, the functions of L1CAM on the OSCC cell proliferation, migration and invasion, and the activation of EMT and PI3K/AKT/ERK signaling pathways were investigated in vitro. Positive L1CAM expression was found in 32.5% of OTSCC cases and was significantly correlated with high histologic grade, greater depth of invasion, lymph node metastasis, perineural invasion, advanced stage, and survival status. Patients with positive L1CAM expression had significantly lower OS rate. Particularly in patients with early OTSCC, L1CAM expression was strongly associated with worse prognosis. Overexpression of the recombinant human L1CAM protein significantly increased cell proliferation, migration and invasion. By contrast, L1CAM knockdown using small interfering RNA significantly inhibited cell proliferation, migration, invasion and EMT. Moreover, phosphorylated (p)-PI3K, p-AKT and p-ERK expression levels were significantly reduced by L1CAM knockdown. Taken together, the findings of the present study suggested that L1CAM could be a potential prognostic marker and a promising therapeutic target in OSCC.

Background There is a lack of understanding of the development of metastasis in lung adenocarcinoma (LUAD). This study is aimed at exploring the upstream regulatory transcription factors of L1 cell adhesion molecule (L1CAM) and to construct a prognostic model to predict the risk of brain metastasis in LUAD. Methods Differences in gene expression between LUAD and brain metastatic LUAD were analyzed using the Wilcoxon rank-sum test. The GRNdb (http://www.grndb.com) was used to reveal the upstream regulatory transcription factors of L1CAM in LUAD. Single-cell expression profile data (GSE131907) were obtained from the transcriptome data of 10 metastatic brain tissue samples. LUAD prognostic nomogram prediction models were constructed based on the identified significant transcription factors and L1CAM. Results Survival analysis suggested that high L1CAM expression was negatively significantly associated with overall survival, disease-specific survival, and prognosis in the progression-free interval (p < 0.05). The box plot indicates that high expression of L1CAM was associated with distant metastases in LUAD, while ROC curves suggested that high expression of L1CAM was associated with poor prognosis. FOSL2, HOXA9, IRF4, IKZF1, STAT1, FLI1, ETS1, E2F7, and ADARB1 are potential upstream transcriptional regulators of L1CAM. Single-cell data analysis revealed that the expression of L1CAM was found significantly and positively correlated with the expression of ETS1, FOSL2, and STAT1 in brain metastases. L1CAM, ETS1, FOSL2, and STAT1 were used to construct the LUAD prognostic nomogram prediction model, and the ROC curves suggest that the constructed nomogram possesses good predictive power. Conclusion By bioinformatics methods, ETS1, FOSL2, and STAT1 were identified as potential transcriptional regulators of L1CAM in this study. This will help to facilitate the early identification of patients at high risk of metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most extremely aggressive cancers with a poor prognosis after curative resection. L1 cell adhesion molecule (L1CAM) is a 200-220 kDa type I transmembrane glycoprotein of the immunoglobulin superfamily, which has been shown to affect the prognosis of several cancers. No clinicopathological significance of L1CAM expression has been examined at the invasive front of PDAC. In this study, we examined the relationship between L1CAM expression and clinicopathological features in PDAC by immunohistochemistry. One hundred seven surgically resected specimens of PDAC were immunohistochemically examined using a monoclonal antibody against L1CAM. Positive expression of L1CAM was found in 23 of 107 cases with PDAC. In most cases (21/23), L1CAM expression was localized at the invasive front of the tumor tissue. Positive expression of L1CAM was significantly correlated with the histological grade, lymph node involvement, and distant metastasis. In univariate analysis, a positive expression of L1CAM was associated with short overall survival (P = 0.0002), and this was significant in multivariate analysis (P = 0.009). L1CAM could play an important role in the invasive process in vivo, and is thought to be a good indicator of prognosis in PDAC.

L1 cell adhesion molecule (L1CAM), which belongs to the immunoglobulin superfamily, has recently been observed in a variety of human malignancies. However, its clinical implication in gastric cancer remains unclear. The aim of this study was to explore the role of L1CAM in gastric cancer and to analyze its correlation with tumor progression and prognosis. L1CAM expression was measured in human gastric cancer cell lines and knockdown was conducted using siRNA. Cell proliferation, invasion and migration ability was assessed in vitro. The downstream pathway of L1CAM was explored by western blot analysis. L1CAM expression was measured in 112 pairs of human gastric cancer and adjacent noncancerous tissues using real-time quantitative RT-PCR, and the correlation with clinicopathological features and prognosis was analyzed. L1CAM downregulation by siRNA significantly decreased cell proliferation, migration, and invasion in gastric cancer cell lines. Phosphorylated ERK levels began to decline more rapidly in L1CAM knockdown cells compared with parental cells. L1CAM overexpression was significantly correlated with local tumor cell growth (P=0.041), distant metastasis (P=0.047), and tumor stage (P=0.031). The overall survival in patients with high L1CAM expression was significantly shorter than that of patients with low L1CAM expression (P=0.02). L1CAM overexpression may be a critical prognostic factor in patients with gastric cancer, and was strongly associated with tumor proliferation, migration, and invasion through the ERK pathway. L1CAM might be an attractive therapeutic molecular target for the treatment of gastric cancer patients.

L1 cell adhesion molecule (L1CAM) expression in endometrial cancer is associated with SRC pathway activation with potential for targeted therapy with dasatinib

ObjectiveTo assess the risk stratification of clinicopathologically and molecularly classified endometrial cancer based on estrogen receptor (ER) and L1 cell adhesion molecule (L1CAM) expression. MethodsThis was a retrospective study of patients who underwent primary treatment at a single tertiary center. Carcinomas were classified into 5 clinicopathological risk groups, as per European guidelines. Immunohistochemistry and polymerase-ϵ sequencing were conducted for molecular classification and determination of ER and L1CAM expression. ResultsData from 1044 patients were analyzed. The median follow-up was 67.5 months. In univariable analyses, ER expression correlated with improved disease-specific survival (DSS) in the “no specific molecular profile” (NSMP) (P < 0.001) and mismatch repair deficient (MMRd) (P = 0.002) subgroups. Negative L1CAM expression was associated with enhanced DSS in the NSMP subgroup alone (P < 0.001). ER (hazard ratio [HR] 0.18), but not L1CAM, exhibited prognostic significance within NSMP when controlling for parameters available at the time of diagnosis (tumor histotype, grade, age). ER and L1CAM were not independently associated with DSS within NSMP when controlling for parameters available after surgery (clinicopathological risk groups, age, adjuvant therapy). However, in high-risk–advanced-metastatic cases, both ER (HR 0.26) and L1CAM (HR 3.9) independently correlated with DSS. Similarly, within MMRd, ER was associated with improved DSS in high-risk–advanced-metastatic carcinomas (HR 0.42). ConclusionThe prognostic significance of ER and L1CAM varies across clinicopathological risk groups and molecular subgroups of endometrial cancer. Notably, risk assessment for high-risk–advanced-metastatic NSMP and MMRd subtype carcinomas can be refined by ER status.