The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread
Abstract
:1. Introduction
2. Methodology
3. Head and Neck Tumors
3.1. Brain
3.1.1. EPHAs
3.1.2. EPHBs
3.1.3. Ephrins
3.2. Salivary Glands
3.3. Thyroid
3.3.1. EPHAs
3.3.2. EPHBs
3.3.3. Ephrins
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
---|---|---|---|---|---|
BRAIN | |||||
EPHA2 | 78 primary glioma samples | IHC |
| [4] | |
21 glioblastoma samples | 5 non-tumorous human brain samples | RT-PCR real-time RT-PCR |
| [5] | |
43 glioma samples | IHC MRI |
| [6] | ||
EPHA4 | 31 GBM samples | 28 non-tumoral white matter samples | q RT-PCR |
| [7] |
EPHA7 | 32 stage IV GBM samples (26 primary, 6 recurrent) | 10 normal brain samples | IHC |
| [8] |
EPHB1 | 171 tumor samples (29 astrocytomas, 82 GBM, 49 oligodendrogliomas, 11 oligoastrocytomas) | 24 non-neoplastic brain samples from epileptogenic patients | q real-time RT-PCR |
| [9] |
EPHB2 | 171 tumor samples (29 astrocytomas, 82 GBM, 49 oligodendrogliomas, 11 oligoastrocytomas) | 24 non-neoplastic brain samples from epileptogenic patients | q real-time RT-PCR |
| [9] |
EPHB3 | 171 tumor samples (29 astrocytomas, 82 GBM, 49 oligodendrogliomas, 11 oligoastrocytomas) | 24 non-neoplastic brain samples from epileptogenic patients | q real-time RT-PCR |
| [9] |
EPHB4 | 171 tumor samples (29 astrocytomas, 82 GBM, 49 oligodendrogliomas, 11 oligoastrocytomas) | 24 non-neoplastic brain samples from epileptogenic patients | q real-time RT-PCR |
| [9] |
96 primary glioma samples | IHC |
| [10] | ||
EPHB6 | 171 tumor samples (29 astrocytomas, 82 GBM, 49 oligodendrogliomas, 11 oligoastrocytomas) | 24 non-neoplastic brain samples from epileptogenic patients | q real-time RT-PCR |
| [9] |
ephrin-A1 | 78 primary gliomas samples | IHC |
| [4] | |
ephrin-B2 | 96 primary glioma samples | IHC |
| [10] | |
ephrin-B3 | 31 GBM samples | 28 non-tumoral white matter samples | q RT-PCR |
| [7] |
7 grade IV glioblastoma samples, 3 glioma samples (1 oligodendroglioma grade II, 1 astrocytoma grade II and 1 astrocytoma grade III) | IHC |
| |||
SALIVARY GLANDS | |||||
EPHA2 | 49 ACC samples | 10 normal salivary gland samples | IHC Western blot real-time RT-PCR |
| [11] |
1 case of ACC | IHC RT-PCR |
| [12] | ||
ephrin-A1 | 49 primary ACC samples | 10 normal salivary gland samples | IHC Western blot real-time RT-PCR |
| [11] |
1 case of ACC | IHC RT-PCR |
| [12] | ||
THYROID | |||||
EPHA2 | 59 thyroid carcinoma samples (47 papillary, 5 follicular, 5 medullary, 2 anaplastic) | 72 benign tissue samples (61 hyperplastic nodules, 11 Hashimoto thyroiditis samples) | IHC |
| [13] |
74 thyroid carcinoma samples (68 papillary, 6 follicular) | 14 follicular adenoma samples | IHC |
| [14] | |
EPHA4 | 59 thyroid carcinoma samples (47 papillary, 5 follicular, 5 medullary, 2 anaplastic) | 72 benign tissue samples (61 hyperplastic nodules, 11 hashimoto thyroiditis samples) | IHC |
| [13] |
EPHB4 | 56 thyroid carcinoma samples (46 papillary, 10 follicular) | 71 benign thyroid tissues (56 hyperplastic nodules, 12 hashimoto thyroiditis tissues) | IHC |
| [15] |
21 papillary carcinoma samples | surrounding normal thyroid samples | cDNA microarray Western blot IHC |
| [16] | |
EPHB6 | 56 thyroid carcinoma samples (46 papillary, 10 follicular) | 71 benign thyroid samples (56 hyperplastic nodules, 12 hashimoto thyroiditis samples) | IHC |
| [15] |
ephrin-B2 | 21 papillary carcinoma samples | surrounding normal thyroid samples | cDNA microarray Western blot IHC |
| [16] |
66 malignant thyroid samples (23 follicular carcinomas, 18 follicular variant of papillary carcinomas, 25 papillary carcinomas) | 4 normal thyroid samples, 26 hyperplastic nodules, 27 follicular adenomas | q real-time PCR | ephrin-B2 mRNA expression elevated in higher TNM stage neoplasms | [17] |
4. Thoracic and Skin Tumors
4.1. Lung
4.1.1. EPHAs
4.1.2. EPHBs
4.2. Breast
4.2.1. EPHAs
4.2.2. EPHBs
4.2.3. Ephrins
4.3. Skin
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
---|---|---|---|---|---|
LUNG | |||||
EPHA1 | 88 NSCLC (56 lung adenocarcinoma, 32 squamous cell carcinoma) | TMA IHC |
| [20] | |
EPHA2 | 225 NSCLC node-negative stage I samples | TMA IHC |
| [21] | |
195 stage I NSCLC samples | Real-time RT-PCR |
| [22] | ||
EPHA4 | 88 NSCLC (56 lung adenocarcinoma, 32 squamous cell carcinoma) | TMA IHC |
| [20] | |
EPHA5 | 88 NSCLC (56 lung adenocarcinoma, 32 squamous cell carcinoma) | TMA IHC |
| [20] | |
EPHA7 | 88 NSCLC (56 lung adenocarcinoma, 32 squamous cell carcinoma) | TMA IHC |
| [20] | |
EPHB1 | 60 NSCLC samples | Non-cancerous tissues | Western blot, IHC |
| [23] |
EPHB2 | 126 lung adenocarcinoma samples | corresponding non-cancerous lung tissues | Quantum dots IHC |
| [24] |
EPHB4 | 93 lung adenocarcinoma samples | IHC |
| [25] | |
ephrin-A1 | 225 NSCLC node-negative stage I samples | TMA IHC |
| [21] | |
195 stage I NSCLC samples | Real-time RT-PCR |
| [22] | ||
244 NSCLC samples | IHC |
| [26] | ||
ephrin-B2 | 93 lung adenocarcinoma samples | IHC |
| [25] | |
ephrin-B3 | 225 NSCLC node-negative stage I samples | TMA IHC |
| [21] | |
BREAST | |||||
EPHA2 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
EPHA4 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
No number mentioned | GOBO and ONCOMINE databases used to investigate EPHA4 mRNA expression and clinical correlations |
| [29] | ||
EPHA7 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
EPHA8 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
EPHB1 | 3554 breast cancer samples | mRNA expression data and survival information from the KM plotter database |
| [30] | |
EPHB2 | Cohort 1: 65 LN positive breast cancer samples | RT-PCR |
| [27] | |
Cohort 2: 216 breast cancer samples | IHC | ||||
3554 breast cancer samples | mRNA expression data and survival information from the KM plotter database |
| [30] | ||
94 breast carcinoma samples | 9 normal breast tissue samples | IHC Semi-quantitative RT-PCR |
| [31] | |
EPHB3 | 3554 breast cancer samples | mRNA expression data and survival information from the KM plotter database |
| [30] | |
EPHB4 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
3554 breast cancer samples | mRNA expression data and survival information from the KM plotter database |
| [30] | ||
94 breast carcinoma samples | 9 normal breast tissue samples | IHC Semi-quantitative RT-PCR |
| [31] | |
216 breast cancer samples | IHC |
| [32] | ||
EPHB6 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
ephrin-A1 | mRNA expression and patients’ survival data from 412 patients from databases | mRNA and survival data analysis |
| [28] | |
TMA IHC in 126 invasive ductal adenocarcinoma samples | 8 normal/benign epithelium samples | TMA IHC | |||
ephrin-B1 | 96 samples | Gene expression data from SAGA and MicMa databases |
| [33] | |
75 breast cancer samples (71 ductal adenocarcinoma, 4 lobular adenocarcinoma) | IHC |
| [34] | ||
ephrin-B2 | 216 breast cancer samples | IHC |
| [32] | |
SKIN | |||||
EPHA1 | 56 basal cell carcinomas, 32 squamous cell carcinomas | 10 normal skin samples | IHC qRT-PCR |
| [35] |
EPHA2 | 202 vertical growth phase melanomas 68 separate samples of local (skin), regional (LNs) and distant metastasis from 58 patients with recurrent disease | TMA IHC |
| [36] | |
ephrin-A1 | 202 vertical growth phase melanomas 68 separate samples of local (skin), regional (LNs) and distant metastasis from 58 patients with recurrent disease | TMA IHC |
| [36] |
5. Gastrointestinal Tract Neoplasia
5.1. Esophagus
5.2. Stomach
5.2.1. EPHAs/Ephrin-As
5.2.2. EPHBs/Ephrin-Bs
5.3. Colon
5.3.1. EPHAs
5.3.2. EPHBs
5.3.3. Ephrins
5.4. Liver
5.5. Biliary Tract
5.6. Pancreas
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
---|---|---|---|---|---|
ESOPHAGUS | |||||
EPHB3 | 141 Barrett’s carcinoma samples | 20 healthy esophagi samples | IHC q PCR |
| [37] |
EPHB4 | 31 samples (GEJ and gastric carcinomas) from 30 patients (1 patient had 1 GEJ carcinoma and 1 gastric cancer in stomach corpus) | Paired normal samples | IHC q RT-PCR |
| [38] |
EPHB6 | 31 samples (GEJ and gastric carcinomas) from 30 patients | Paired normal samples | IHC q RT-PCR |
| [38] |
STOMACH | |||||
EPHA2 | 176 gastric adenocarcinoma samples | Paired adjacent normal tissues | Real-time RT-PCR IHC Western blot |
| [39] |
46 adenocarcinomas, 2 adenosquamous carcinomas, 1 neuroendocrine carcinoma | Corresponding non-tumor samples | Semiquantitative RT-PCR IHC Western blot |
| [40] | |
91 gastric adenocarcinomas | 7 gastrointestinal stromal tumor samples | IHC Western blot |
| [41] | |
107 gastric adenocarcinoma samples (54 of them received adjuvant chemotherapy) | Normal paired gastric samples | Proteome analysis (LC-MS/MS) mRNA (real-time RT-PCR) IHC |
| [44] | |
EPHA4 | 24 paired fresh gastric adenocarcinoma samples, 74 fresh frozen paraffin embedded gastric adenocarcinoma samples, 55 gastric adenocarcinoma samples in tissue microarrays | Adjacent non-tumor samples from 24 gastric adenocarcinoma specimens | Real-time RT-PCR RT-PCR IHC |
| [42] |
EPHA5 | 107 gastric adenocarcinoma samples (54 of them received adjuvant chemotherapy) | Normal paired gastric samples | Proteome analysis (LC-MS/MS) mRNA (real-time RT-PCR) IHC |
| [44] |
EPHA8 | 206 gastric cancer samples | 32 normal gastric mucosa, 60 paracancerous samples | IHC Western blot |
| [43] |
EPHB2 | 107 gastric adenocarcinoma samples (54 of them received adjuvant chemotherapy) | Normal paired gastric samples | Proteome analysis (LC-MS/MS) mRNA (real-time RT-PCR) IHC |
| [44] |
EPHB4 | 107 gastric adenocarcinoma samples (54 of them received adjuvant chemotherapy) | Normal paired gastric samples | Proteome analysis (LC-MS/MS) mRNA (real-time RT-PCR) IHC |
| [44] |
31 gastric and GEJ carcinomas | Paired normal samples | Quantitative real-time RT-PCR IHC |
| [38] | |
EPHB6 | 31 gastric and GEJ carcinomas | Paired normal samples | Quantitative real-time RT-PCR IHC |
| [38] |
152 gastric carcinoma samples | IHC | EPHB6 expression:
| [46] | ||
ephrin-A1 | 176 gastric adenocarcinoma samples | Paired adjacent normal samples | Real-time RT-PCR IHC Western blot |
| [39] |
46 adenocarcinomas, 2 adenosquamous carcinomas, 1 neuroendocrine carcinoma | Paired non-tumor samples | Semiquantitative RT-PCR IHC Western blot |
| [40] | |
ephrin-B1 | 29 gastric carcinoma samples | Matched normal samples | Semiquantitative RT-PCR |
| [45] |
COLON | |||||
EPHA1 | 53 CRC samples | adjacent normal samples | IHC q real-time PCR |
| [48] |
125 CRC specimens, 53 paired normal colon-CRC samples | 18 normal colon samples, paired normal samples from the 53 CRC patients | q real-time PCR Flow cytometry Western blot IHC |
| [49] | |
EPHA2 | 53 CRC samples | adjacent normal samples | IHC q real-time PCR |
| [48] |
37 CRC samples | 37 paired normal samples | IHC Semi-quantitative RT-PCR |
| [50] | |
EPHA3 | 53 CRC samples | adjacent normal tissues | IHC q real-time PCR |
| [48] |
68 CRC samples | paired adjacent normal mucosa | IHC |
| [51] | |
EPHA7 | 53 CRC samples | adjacent normal samples | IHC q real-time PCR |
| [48] |
EPHB2 | 345 primary CRCs 98 LN metastasis 82 liver metastasis | 100 adenomas 111 normal mucosa | IHC |
| [54] |
159 samples of stage 3 CRC | IHC |
| [55] | ||
28 primary CRCs 39 metastasis 342 paired primary CRCs and normal samples in tissue microarrays | 28 normal colon samples 148 colorectal adenomas | IHC |
| [56] | |
4000 samples from 138 different tumor types, 1476 samples of colon cancer | 76 different normal samples | IHC |
| [57] | |
36 CRCs | 30 Dysplastic aberrant foci, (dACF) 31 small (<5 mm) adenomas, 12 large (>5 mm) adenomas | IHC |
| [58] | |
EPHB3 | 610 CRC samples formalin-fixed 32 fresh colorectal cancer samples | IHC q real-time PCR |
| [59] | |
EPHB4 | 20 colon carcinoma samples | adjacent uninvolved mucosa | IHC RT-PCR |
| [53] |
200 CRC samples | 50 adjacent non-tumor samples | IHC |
| [60] | |
ephrin-A1 | 53 CRC samples | adjacent normal samples | IHC q real-time PCR |
| [48] |
37 CRC samples | 37 paired normal samples | IHC Semi-quantitative RT-PCR |
| [50] | |
ephrin-A5 | 53 CRC samples | adjacent normal samples | IHC Quantitative real-time PCR |
| [48] |
72 colon malignancies (68 adenocarcinomas, 4 non-Hodgkin lymphomas) | 10 normal colon samples 14 benign colon lesions (adenomas and polyps) | IHC Western blot q real-time PCR RT-PCR |
| [52] | |
ephrin-B2 | 20 colon carcinoma samples | adjacent uninvolved mucosa | IHC RT-PCR |
| [53] |
200 CRC samples | 50 adjacent non-tumor samples | IHC |
| [60] | |
LIVER | |||||
EPHA1 | 20 HCC samples | Non-cancerous adjacent tissues | IHC Northern blot |
| [61] |
EPHA2 | 139 HCC samples | Real-time q RT-PCR |
| [63] | |
40 HCC samples | Cirrhotic non-tumorous samples | IHC Northern blot RT-PCR |
| [62] | |
EPHA5 | 250 HCC samples | Paired normal samples | IHC |
| [64] |
ephrin-A1 | 20 HCC samples | Non-cancerous adjacent samples | IHC Northern blot |
| [61] |
139 HCC samples | Real-time q RT-PCR |
| [63] | ||
40 HCC samples | Cirrhotic non-tumorous samples | IHC Northern blot RT-PCR |
| [62] | |
ephrin-A5 | 142 paired HCC and peritumoral liver samples | Paired peritumoral samples | Real-time q RT-PCR |
| [65] |
BILIARY TRACT | |||||
EPHA2 | 30 ICC samples, 5 LN metastasis from 5 of the above patients | Normal adjacent samples | PCR-based Sanger sequencing |
| [66] |
EPHB2 | 50 cholangiocarcinoma samples | IHC | High
| [67] | |
EPHB4 | 50 cholangiocarcinoma patients | IHC |
| [67] | |
ephrin-B1 | 50 cholangiocarcinoma samples | IHC | High
| [67] | |
ephrin-B2 | 50 cholangiocarcinoma samples | IHC |
| [67] | |
PANCREAS | |||||
ephrin-B2 | 179 PDAC samples (mRNA data) | 171 normal pancreatic samples (mRNA data) | Statistical analysis | Data analysis of mRNA expression of the 179 PDAC and 171 normal pancreatic tissues showed that:
| [68] |
54 PDAC samples | 54 adjacent normal samples | IHC Quantitative real-time PCR Western blot |
IHC, qRT-PCR and western blot analysis of the 54 PDAC tissues showed that:
|
6. Urinary Tract Neoplasia
6.1. Kidney
6.1.1. EPHAs
6.1.2. EPHBs/Ephrins
6.2. Bladder
6.2.1. EPHAs
6.2.2. EPHBs
6.2.3. Ephrins
6.3. Prostate
6.3.1. EPHAs
6.3.2. EPHBs/Ephrin-Bs
KIDNEY | |||||
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
EPHA1 | mRNA from 75 malignant samples | matched non-malignant samples | q PCR |
| [69] |
protein expression from 241 malignant samples (primary and metastatic) | non-malignant samples | TMA IHC | |||
EPHA2 | mRNA from 75 malignant samples | matched non-malignant samples | q PCR |
| [69] |
protein expression from 241 malignant samples (primary and metastatic) | non-malignant samples | TMA IHC | |||
EPHA3 | 68 CCRCC samples | adjacent normal kidney samples | IHC |
| [70] |
EPHB4 | 12 kidney cancer samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] | |
ephrin-A1 | mRNA from 75 malignant samples | matched non-malignant samples | q PCR |
| [69] |
protein expression from 241 malignant samples | non-malignant samples | TMA IHC | |||
ephrin-B2 | 12 kidney cancer samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] | |
BLADDER | |||||
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
EPHA2 | 64 TCC samples | 13 normal urothelium samples | IHC |
| [72] |
EPHB2 | 40 bladder TCC samples | adjacent non-tumorous samples | IHC Western blot |
| [73] |
EPHB4 | 40 bladder TCC samples | adjacent non-tumorous samples | IHC Western blot |
| [73] |
33 bladder cancer samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] | ||
ephrin-A1 | 64 TCC samples | 13 normal urothelium samples | IHC |
| [72] |
ephrin-B2 | 410 bladder TCC samples | Ephrin-B2 expression data from the cancer genome atlas (TCGA) |
| [74] | |
33 bladder cancer samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] | ||
PROSTATE | |||||
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
EPHA5 | 22 PCa samples, 23 paired cancerous and non-cancerous samples | 39 BPH samples, 23 paired non-cancerous samples | IHC q RT-PCR Methylation-specific PCR |
| [75] |
EPHA6 | 112 PCa tumor samples | 58 BPH samples | q real-time PCR |
| [76] |
EPHB4 | 20 PCa samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] | |
ephrin-B2 | 20 PCa samples | IHC staining of arterial and venous vessels in tumoral and non-tumoral tissues |
| [71] |
7. Gynecological Tumors
7.1. Ovary
7.1.1. EPHAs
7.1.2. EPHBs
7.1.3. Ephrins
7.2. Endometrium
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
---|---|---|---|---|---|
OVARY | |||||
EPHA1 | 24 ovarian carcinoma samples | 4 benign ovarian samples | q real-time RT-PCR |
| [77] |
EPHA2 | 24 ovarian carcinoma samples | 4 benign ovarian samples | q real-time RT-PCR |
| [77] |
118 EOC samples | IHC RT-PCR |
| [78] | ||
EPHA5 | 61 ovarian serous carcinoma samples | 24 benign ovarian serous tumors, 42 serous borderline ovarian tumors, 20 normal fallopian tubes | IHC |
| [79] |
EPHA8 | 20 fresh-frozen specimens: 20 EOC samples | 40 fresh frozen samples: 20 normal ovarian samples, 20 normal fallopian tube samples | q RT-PCR |
| [80] |
125 paraffin-embedded EOCs | 98 samples paraffin-embedded: 30 borderline samples, 30 benign ovarian tumors, 20 normal fallopian tubes, 18 normal ovarian samples | TMA IHC | |||
EPHB3 | 50 ovarian serous carcinomas | 17 serous borderline tumors, 19 normal fallopian tubes | IHC |
| [81] |
EPHB4 | 72 ovarian cancer samples | IHC Real-time RT-PCR |
| [82] | |
ephrin-A1 | 24 ovarian carcinoma samples | 4 benign ovarian samples | q real-time RT-PCR |
| [77] |
ephrin-A5 | 24 ovarian carcinoma samples | 4 benign ovarian samples | q real-time RT-PCR |
| [77] |
ephrin-B1 | 27 serous adenoCa, 14 mucinous adenoCa, 15 clear cell adenoCa, 15 endometrioid adenoCa | 11 serous cystadenomas, 5 mucinous cystadenomas, 10 serous borderline tumors, 15 muscinous borderline tumors | IHC Western blot |
| [83] |
ephrin-B2 | 72 ovarian cancer samples | IHC Real-time RT-PCR |
| [82] | |
ENDOMETRIUM | |||||
EPHA2 | 139 endometrial endometrioid carcinoma samples | 10 benign endometrial | IHC |
| [84] |
EPHB4 | 68 endometrial cancer samples | 16 normal endometrium samples | IHC Real-time RT-PCR |
| [85] |
11 ER (+)/PR (+) endometrial carcinoma samples, 33 ER (-)/PR (-) endometrial carcinoma samples | 10 adenomyosis samples, 2 simple endometrial hyperplasia samples, 20 atypical endometrial hyperplasia samples | IHC Western blot |
| [86] | |
ephrin-B2 | 68 endometrial cancer samples | 16 normal endometrium samples | IHC Real-time RT-PCR |
| [85] |
11 ER (+)/PR (+) endometrial carcinoma samples, 33 ER (-)/PR (-) endometrial carcinoma samples | 10 adenomyosis samples, 2 simple endometrial hyperplasia samples, 20 atypical endometrial hyperplasia samples | IHC Western blot |
| [86] | |
CERVIX | |||||
EPHA2 | 206 squamous cell cervical cancer samples | IHC |
| [87] | |
217 early squamous cell cervical carcinoma samples | IHC |
| [88] | ||
EPHB2 | 20 HGSIL, 53 cervical squamous cell carcinomas | 25 normal cervical samples | IHC |
| [89] |
EPHB4 | 90 cervical carcinoma samples, 15 CIN samples | 15 normal cervix samples | IHC |
| [90] |
62 uterine cervical cancer samples | IHC Real-time RT-PCR |
| [82] | ||
ephrin-A1 | 206 squamous cell cervical cancer samples | IHC |
| [87] | |
217 early squamous cell cervical carcinoma samples | IHC |
| [88] | ||
ephrin-B2 | 90 cervical carcinoma samples, 15 CIN samples | 15 normal cervix samples | IHC |
| [90] |
62 uterine cervical cancer samples | IHC Real-time RT-PCR |
| [82] |
7.3. Cervix
8. Pediatric Neoplasia
8.1. Sarcomas
8.2. Neuroblastoma
8.3. Wilms Tumor
EPHs/Ephrins | Malignant Tissues | Benign Control Tissues | Methods | Results | Refs |
---|---|---|---|---|---|
RHABDOMYOSARCOMA | |||||
EPHA2 | 14 ERM samples | normal skeletal muscle samples | real-time RT-PCR |
| [91] |
EPHB4 | Not mentioned | Data from the Intergroup Rhabdomyosarcoma Study Group (IRSG)-IV Affymetrix U95 GeneChip database regarding EphB4 expression in human ERMs |
| [92] | |
ephrin-A1 | 14 ERM samples | normal skeletal muscle samples | real-time RT-CR |
| [91] |
NEUROBLASTOMA | |||||
EPHB6 ephrin-B2 ephrin-B3 | 50 neuroblastoma samples | q RT-PCR |
| [93] | |
WILMS TUMOR | |||||
EPHB2 | 25 primary Wilms tumor samples | q PCR |
| [94] |
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
EPH | erythropoietin-producing human hepatocellular receptors |
Ephrin | EPH family receptor interacting proteins |
RTK | receptor tyrosine kinases |
IHC | immunohistochemistry |
TMA | tissue microarrays |
PCR | polymerase chain reaction |
RT-PCR | reverse transcription-polymerase chain reaction |
q PCR | quantitative reverse transcription- polymerase chain reaction |
LN | lymph nodes |
OS | overall survival |
DFS | disease-free survival |
MVD | microvessel density |
GBM | glioblastoma |
ACC | adenoid cystic carcinoma |
EMT | epithelial-mesenchymal transition |
NSCLC | non-small-cell lung carcinoma |
EGFR | epidermal growth factor receptor |
CRC | colorectal carcinoma |
HCC | hepatocellular carcinoma |
PDAC | pancreatic ductal adenocarcinoma |
CCRCC | clear cell renal cell carcinoma |
TCC | transitional cell carcinoma |
PCa | prostate carcinoma |
BPH | benign prostate hyperplasia |
EOC | epithelial ovarian carcinoma |
SCC | squamous cell carcinoma |
ERM | embryonal rhabdomyosarcoma |
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Therapeutic Agent | Target | Category | Malignancy | Reference |
---|---|---|---|---|
DS-8895a | EPHA2 | Antibody, antagonist | Esophageal and gastric cancer | [95] |
Ifabotuzumab (KB004) | EPHA3 | Antibody, antagonist | Hematologic malignancies | [95] |
MEDI-547 | EPHA2 | Antibody-drug conjugate, agonist | Solid tumors (various) | [95] |
PF-06647263 | ephrin-A4 | Antibody-drug conjugate, antagonist | Ovarian and breast cancer (majority) | [95] |
sEphB4-HSA | ephrin-B2 | Protein complex, antagonist | Solid and hematologiccancers | [96,97] |
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Pergaris, A.; Danas, E.; Goutas, D.; Sykaras, A.G.; Soranidis, A.; Theocharis, S. The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread. Int. J. Mol. Sci. 2021, 22, 8412. https://doi.org/10.3390/ijms22168412
Pergaris A, Danas E, Goutas D, Sykaras AG, Soranidis A, Theocharis S. The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread. International Journal of Molecular Sciences. 2021; 22(16):8412. https://doi.org/10.3390/ijms22168412
Chicago/Turabian StylePergaris, Alexandros, Eugene Danas, Dimitrios Goutas, Alexandros G. Sykaras, Angelos Soranidis, and Stamatios Theocharis. 2021. "The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread" International Journal of Molecular Sciences 22, no. 16: 8412. https://doi.org/10.3390/ijms22168412