Clinical Significance of Nectins in HCC and Other Solid Malignant Tumors: Implications for Prognosis and New Treatment Opportunities—A Systematic Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Literature Research
3. Nectin-1
Authors | Cancer | Material | Results and Conclusions |
---|---|---|---|
Wang et al. [20] | HCC | 28 paired samples—cancerous and non-cancerous tissue. Additionally, gene expression data (TCGA) | High nectin-1 expression in cancer compared to adjacent tissues. Up-regulation of nectin-1 correlated with a worse prognosis and more advanced disease. |
Martin et al. [21] | BrC | 133 breast cancer tissues, 27 control cancer-free breast tissues | Nectin-1 expression was elevated in tumors, especially tumors with a higher TNM stage, tumor grade and NPI, ductal carcinomas and ER+ tumors. Higher expression was an indicator of poor survival (but the difference was not significant). |
Yamada et al. [22] | PDAC | Carcinoma-associated-fibroblasts (CAF) in 258 samples | Nectin-1 expressed in 64 tumors, correlated with lymph node metastasis (N1-2), IIB-IV TNM stage, perineural invasion, tumor location in the pancreatic head and shorter OS. |
Izumi et al. [23] | PAC | 49 cancer samples | Nectin-1 was highly expressed in the cancer tissues, but no correlation with OS was found. |
Tampakis et al. [24] | CRC | 111 tissue samples | High expression of nectin-1 in 59.5% of tumors. Significantly higher expression in advanced tumors (stage III–IV). Lymph node metastasis correlates with a high expression of nectin-1. Nectin-1 was an independent prognostic factor of disease recurrence and death. |
Takahashi et al. [25] | GC | 406 patients’ data from TCGA Samples resected surgically and endoscopically (89 and 81, respectively) | Low expression of nectin-1 indicates poor survival (median 25.6 months vs. 55.4 months in the case of a high expression). |
Ahn et al. [26] | BUC | 165 tissue samples | Nectin-1 expression was an independent predictive factor of worse OS. |
Han et al. [27] | LGG | TCGA, CGGA and REMBRAND databases | Low expression of nectin-1 was a predictor of worse prognosis. |
Kälin et al. [28] | mCRPC | 57 serum samples | A higher level of nectin-1 was one of predictors of worse survival (in the set of 5 proteins). |
4. Nectin-2
Authors | Cancer | Material | Results and Conclusions |
---|---|---|---|
Huang et al. [30] | HCC | 159 tissue samples (cancerous and adjacent tissue) | Low expression of nectin-2 was associated with poorer OS but was not an independent prognostic factor. |
Martin et al. [21] | BrC | 133 breast cancer tissues, 27 control cancer-free breast tissues | Nectin-2 was reduced in tumors with positive lymph nodes and metastasis, increasing NPI and tumor grade. The expression was elevated with higher TNM (I vs. III), ER tumors and in ductal carcinoma. Patients who died from the disease had reduced expression of nectin-2. High-expressing patients had longer mean survival. |
Zhang et al. [32] | CRC | 42 cancer samples | Nectin-2 expressed in 52.4% samples, no association between expression and clinicopathological data. |
Karabulut et al. [34] | CRC | 140 serum samples | Nectin-2 concentrations were generally higher among CRC patients. Among non-metastatic patients, higher levels of nectin-2 indicated worse PFS. |
Wang et al. [35] | GC | 670 tissue samples | Nectin-2 was expressed in 90% of GC samples and was related to OS. The scoring system created (including nectin-2) was an independent marker of worse prognosis. |
Xu et al. [36] | GC | 150 tissues and blood samples, GC cell lines and TCGA data | Nectin-2 was overexpressed in GC and correlated with poorer survival of the patients. |
Li et al. [37] | ESCC | 106 tissue samples, cell lines | Nectin-2 was overexpressed in tumor tissue compared to normal mucosa. Over 70% of tumors expressed nectin-2 highly and moderately. Higher expression was related to features indicating poorer survival—tumor size, stage and differentiation. |
Liang et al. [38] | PDAC | 106 cancer tissues, 35 peritumoral tissues, 55 benign pancreatic lesions, 13 normal pancreatic tissues | Nectin-2 was expressed in 54.7% of cancers, while higher percentages were observed in more aggressive tumors. Nectin-2 is an independent prognostic factor of shorter OS. |
Izumi et al. [23] | PAC | 49 cancer samples | Nectin-2 was weakly expressed and correlated only with tumors’ grade. No connection with OS was established. |
Bekes et al. [39] | OC | 60 ovarian cancer samples, 20 healthy controls | Nectin-2 was highly expressed in OC, with especially high expression in TNM N+ tumors (indicating possible prognostic value). |
Ni et al. [40] | OC | 132 urine samples—73 malignant and 59 benign lesions | Classifier created (based on WFDC2, PTMA, nectin-4, FIBA, and nectin-2) to distinguish benign from malignant lesions with AUC=0.952 in ROC analysis. |
Wang et al. [41] | BC | 1603 patients—Surveillance, Epidemiology and End Results (SEER) database | NECTIN2 was the only gene which could predict metastasis. |
Erturk et al. [42] | LC | 74 LC patients’ serum samples, 40 controls | Nectin-2 served as a biomarker with 91.9% sensitivity and 92.5% specificity in the study. |
5. Nectin-3
6. Nectin-4
Authors | Cancer | Material | Results and Conclusions |
---|---|---|---|
Ma et al. [46] | HCC | 20 tumor specimens and adjacent non-tumor fragments (mRNA and protein—Western blot) 87 tumor samples (IHC) | Nectin-4 was expressed in ~65–70% of tumors and positive nectin-4 status was an independent prognostic factor for shorter RFS and OS. |
Lattanzio et al. [47] | BrC | 197 tumor samples | A membranous pattern of nectin-4 expression was an independent prognostic factor of worse DFS in luminal-A BrC. Low cytoplasmic expression was also a prognostic factor influencing LRFS in general and DFS in luminal-A tumors. |
Rajc et al. [48] | BrC | 147 tumor samples | High nectin-4 expression was associated with all survival models, but was established as a risk factor for OS and DFS in luminal-B tumors. |
M-Rabet et al. [49] | BrC | 353 samples (for DNA microarrays) 61 samples (for IHC) 5673 patients’ data (from an outside database) | High nectin-4 expression was a negative prognostic factor for MFS in patients with TNBC. |
Zeindler et al. [50] | BrC | 148 tumor samples | High expression of nectin-4 predicted better survival, and was associated with favorable pathological features in TNBC. |
Sethy et al. [51] | BrC | 100 tumor samples | Nectin-4 was highly expressed in 92% of samples and was linked to unfavorable disease characteristics—lymph node metastasis, tumor size and grade. |
Tomiyama et al. [54] | UTUC | 99 tumor samples | Nectin-4 expressed in 65.7% of samples and was a negative prognostic factor of PFS, and was linked to higher mortality. |
Zhang et al. [55] | CRC | 372 CRC samples and 31 normal samples from TCGA 68 CRC and 15 normal paraffin samples | Nectin-4 showed high expression in most of the tumors and suggested potential prognostic value, because it correlated with TNM stage, lymph nodes and distant metastasis (but not T stage). |
Deng et al. [56] | EC | TCGA datasets 94 cancer tissues and 78 normal tissues | Nectin-4 had strong expression in EC in IHC staining, but a low mRNA expression. Both aforementioned features indicated worse OS, but a higher expression in IHC was significantly correlated with OS and was suggested as a prognostic factor. |
Lin et al. [57] | EC | 94 cancer specimens | Nectin-4 was mostly overexpressed in cancer, and higher expression correlated with worse OS and was a prognostic factor. |
Zhang et al. [58] | GC | 20 paired cancer/healthy tissues 303 cancer specimens 91 adjacent normal tissues | Nectin-4 was expressed in 60% of cancers. High expression was a negative prognostic factor for OS. |
Zhang et al. [59] | GC | 64 paired cancer/healthy samples | Nectin-4 was highly expressed in 70% of samples and was correlated with shorter 5-year survival. |
Nabih et al. [60] | OC | 39 patients with OC 21 patients with benign lesions (25 control benign biopsies) | Nectin-4 was increased in malignant compared to benign lesions. Combined nectin-4 mRNA with CA-125 showed the highest sensitivity in discriminating malignant from benign tumors. Nectin-4 was suggested as a marker for diagnosis and treatment monitoring. |
Bekos et al. [61] | OC | 90 samples of HGSOC | High expression of nectin-4 was an independent prognostic factor of worse OS. |
Hao et al. [62] | PTC | 19 + 44 thyroid cancer tissues with adjacent tissue | Nectin-4 was upregulated in tumors and correlated with disease stage (and N stage), tumor size and histological type. |
Toda et al. [63] | ATC | 54 samples | Nectin-4 was highly expressed in tumors and was associated with more aggressive cancers. |
Tanaka et al. [64] | Melanoma | 126 melanoma samples | A high level of nectin-4 was significantly associated with BRAF mutation and worse DFS, melanoma-specific survival and OS, and therefore also indicated poor prognosis. |
Murata et al. [65] | EMPD | 110 EMPD samples | Up-regulated nectin-4 was associated with higher TNM and thicker tumors, but had no impact on survival. |
Erturk et al. [42] | LC | 74 LC patients’ serum samples, 40 controls | The serum nectin-4 was elevated in LC patients and correlated with NSCLC stage, the tumor size and metastasis, but was not prognostic. |
Zhang et al. [66] | GBC | 68 cancer samples 60 cholecystitis tissues | Nectin-4 was an independent prognostic factor and indicated poorer OS in GBC. Overexpression correlated with T stage and lymph nodes metastasis. |
Nishiwada et al. [67] | PDAC | 123 cancer samples | Higher nectin-4 expression was associated with increased Ki-67 and poorer survival. Multivariate analysis showed that overexpression of nectin-4 was an independent prognostic factor. |
7. Discussion
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Nectin | Binding Partners | Function |
---|---|---|
Nectin-1 | nectin-1, nectin-3, nectin-4, necl-1, CD96 | Cell adhesion, immune modulation, viral entry receptor |
Nectin-2 | nectin-2, TIGIT, CD226 | Cell adhesion, immune modulation, viral entry receptor |
Nectin-3 | nectin-3, nectin-1, nectin-2, necl-2, necl-5, TIGIT | Cell adhesion, immune modulation |
Nectin-4 | nectin-4, nectin-1 | Cell adhesion, viral entry receptor |
Authors | Cancer | Material | Results and Conclusions |
---|---|---|---|
Martin et al. [21] | BrC | 133 breast cancer tissues, 27 control cancer-free breast tissues | Expression was reduced in more advanced tumors. Patients with higher expressing tumors had better outcomes. |
Izumi et al. [23] | PAC | 49 cancer samples | Higher expression of nectin-3 was an independent prognostic factor of better OS. |
Hirabayashi et al. [43] | PanNET | 78 tumor tissue samples | Loss of nectin-3 expression was a prognostic factor of worse prognosis—shorter DFS—but it was not statistically significant in multivariate analysis. |
Xu et al. [44] | OC | 74 OC tissue specimens 24 BOT tissues 34 BOET tissues | Nectin-3 was expressed in 35% of OC specimens and was a risk factor of shorter survival. |
Maniwa et al. [45] | LAC | 127 cancer tissues | Nectin-3 was expressed in 81% of cancers and in 25%, it was expressed in the membranes, which was an independent negative prognostic factor. |
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Klekowski, J.; Zielińska, D.; Hofman, A.; Zajdel, N.; Gajdzis, P.; Chabowski, M. Clinical Significance of Nectins in HCC and Other Solid Malignant Tumors: Implications for Prognosis and New Treatment Opportunities—A Systematic Review. Cancers 2023, 15, 3983. https://doi.org/10.3390/cancers15153983
Klekowski J, Zielińska D, Hofman A, Zajdel N, Gajdzis P, Chabowski M. Clinical Significance of Nectins in HCC and Other Solid Malignant Tumors: Implications for Prognosis and New Treatment Opportunities—A Systematic Review. Cancers. 2023; 15(15):3983. https://doi.org/10.3390/cancers15153983
Chicago/Turabian StyleKlekowski, Jakub, Dorota Zielińska, Adriana Hofman, Natalia Zajdel, Paweł Gajdzis, and Mariusz Chabowski. 2023. "Clinical Significance of Nectins in HCC and Other Solid Malignant Tumors: Implications for Prognosis and New Treatment Opportunities—A Systematic Review" Cancers 15, no. 15: 3983. https://doi.org/10.3390/cancers15153983