{"paper_id":"62f3ff65-719c-4724-b74a-862cb60f17a8","body_text":"Introduction: Endometrial carcinoma \nis now considered a common female \ngynecologic cancer with increasing in-\ncidence, with 13–25% of patients being \nstill liable to recurrence and metasta-\nsis, which needs further studies to de-\ntect novel targets and new therapies. \nThe aim of the study was evaluate \ntissue expression of RON, ROR1 and \nSUSD2 in endometrial carcinoma and \natypical endometrial hyperplasia using \nimmunohistochemistry and correlate \ntheir expression with clinical, patho-\nlogical and prognostic parameters  \nof patients.\nMaterial and methods: We included \nsamples from 100 patients with en-\ndometrial carcinoma. Sections from \nparaffin blocks were stained with \nRON, ROR1 and SUSD2 using immuno-\nhistochemistry. Correlations between \nmarker expression, clinicopathological \nfeatures and prognostic samples were \nevaluated.\nResults: Upregulation of RON and \nROR1 and downregulation of SUSD2 \nexpression were found in endome-\ntrial carcinoma more than atypical \nendometrial hyperplasia (p  < 0.001). \nHigh RON and ROR1 expression levels \nwere significantly associated with high \ngrade (p < 0.001), presence of lymph \nnode metastases (p  = 0.003), distant \nmetastases (p = 0.009), advanced In-\nternational Federation of Gynecology \nand Obstetrics stage (p = 0.002), poor \nresponse to therapy (p  = 0.046), and \nlower recurrence-free survival (RFS) \nrate (p = 0.002), progression-free sur-\nvival (PFS) rate (p  = 0.008), distant \nmetastasis-free survival (DMFS) rate \n(p = 0.019) and overall survival rate  \n(p < 0.001). Low SUSD2 expression was \nsignificantly associated with older pa-\ntient age (p = 0.002), large tumor size  \n(p = 0.003), high grade (p  = 0.005), \npresence of adnexal invasion (p = 0.023), \npresence of lympho-vascular invasion  \n(p = 0.021), extent of myometrial in-\nvasion (p  = 0.002), lower RFS rate  \n(p = 0.008), lower PFS rate (p = 0.023), \nand lower DMFS rate (p < 0.001).\nConclusions: Upregulation of RON and \nROR1 and downregulation of SUSD2 \nlead to promotion of endometrial can-\ncer cell proliferation, migration, epi-\nthelial-mesenchymal transition, and \ninvasion.\nKey words: endometrial carcinoma, \nRON, ROR1 and SUSD2, prognosis.\nContemp Oncol (Pozn) 2022; 26 (2): 109–122\nDOI: https://doi.org/10.5114/wo.2022.118245\nOriginal paper\nRON, ROR1 and SUSD2 expression \nin tissues of endometrial carcinoma \npatients. Clinicopathological  \nand prognostic implications\nAbeer M. Abdelbary1, Randa Mohamed Kaf1, Mohamed Elbakry Lashin2, \nAhmed Z. Alattar3, Dalia Hamouda Elsayed3, Ahmed F. Amin4,  \nLoay M. Gertallah5, Ahmed Mohamed Yehia6\n1Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt \n2Gynecology and Obstetrics Department, Faculty of Medicine, Zagazig University, \n Zagazig, Egypt  \n3Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Zagazig \n University, Zagazig, Egypt  \n4Medical OncologyDepartment, Faculty of Medicine, Zagazig University, Zagazig, Egypt  \n5Anesthesia and Intensive care Department, Faculty of Medicine, Zagazig University, \n Zagazig, Egypt  \n6General Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt\nIntroduction\nEndometrial carcinoma is now considered a common female gynecologic can-\ncer with increasing incidence in developed countries. It usually has good prog-\nnosis but 13–25% of patients are still liable to recurrence and metastasis [1, 2], \nwhich needs further studies for detecting novel targets and new therapies.\nCancer invasion and metastasis is responsible for poor patients’ progno-\nsis [3], and epithelial-mesenchymal transition (EMT) has vital roles in such \nprocesses [4].\nEpithelial-mesenchymal transition is the biological process by which epi-\nthelial cells lose their normal criteria and acquire mesenchymal properties, \nthus enabling them to invade and metastasize [5], promoting cancer pro-\ngression and spread [6]. \nThe tyrosine kinase receptor which is known as recepteur d’origine nantais \n(RON), discovered in 1993, has been found to be overexpressed in many can-\ncers [7, 8]. RON overexpression was associated with metastasis and poor prog-\nnosis [9]. Epithelial-mesenchymal transition, which explained invasion, metas-\ntases and progression of many cancers, was found to be mediated by several \nmediators as RON, ROR1 and SUSD2 (sushi domain containing 2) [10–12].\nRON aberrant expression induces EMT in tumor cells, thus allowing mi-\ngration, invasion and metastases [10]. So, targeting RON could be a promis-\ning cancer targeted therapy.\nAlthough the role of RON in cancer progression has been studied in many \ncancers, its prognostic roles in endometrial adenocarcinoma have not been \nsufficiently clarified. \nThe recently detected Wnt receptor, ROR1 which is a tyrosine kinase-like \norphan receptor, plays critical roles in embryogenesis. Aberrant ROR1 expres-\nsion has been found in many cancers [11, 13]. ROR1 has various oncogenic \nroles in cancers [14].\nIt plays an oncogenic role in many tumors by increasing tumor prolifera-\ntion, stimulating stemness [15], and activating EMT [12].\nSUSD2 was primarily detected in mouse as a tumor-reversing gene. \nHuman SUSD2 is located on chromosome 22 and encodes an 822-mino \nacid type I membrane protein containing Sushi domains, which play import-\nant roles in adhesions between cells and cell-matrix adhesion [16]. Recent-\n\n110\ncontemporary oncology\nly, dysregulated expression of SUSD2 was found in many \ncancers and associated with cancer progression, pointing \nto its oncosuppressive roles in cancers.\nThe aim of this study was to evaluate tissue expres-\nsion of RON, ROR1 and SUSD2 in endometrial carcinoma \nand atypical endometrial hyperplasia using immunohis-\ntochemistry and correlate their expression with clinical, \npathological and prognostic parameters of patients.\nMaterial and methods\nIn the present study we included samples from 100 pa-\ntients with endometrial carcinoma.\nCases were primarily collected by endometrial biopsy \nin the Gynecology and Obstetrics Department diagnosed \nin the Pathology Department. Cases underwent the ope-\nrations of total abdominal hysterectomy and bilateral  \nsalpingo-oophorectomy with or without lymphadenectomy \nin the Gynecology and Obstetrics Department and General \nSurgery Department, Faculty of Medicine, Zagazig Univer-\nsity Hospitals. All surgically operated samples were sent \nto the Pathology Department for final diagnosis, grading \nand staging.\nPatients were sent to the Medical Oncology Department \nand to Clinical Oncology and Nuclear Medicine for further \nmanagement and follow-up for survival and recurrence.\n We included 100 tissue blocks containing samples from \npatients with endometrial carcinoma and adjacent tissues \nof atypical endometrial hyperplasia.\nExclusion criteria\nCases with insufficient material in paraffin blocks and \ncases diagnosed with other endometrial malignancies \nsuch as endometrial stromal sarcoma and leiomyosarco-\nma were excluded.\nImmunohistochemistry\nFor immunohistochemistry sections were incubated \nwith primary anti-RON (1 : 500; ab52927; Abcam, Cam-\nbridge, Cambridgeshire, UK), anti-ROR1 (1 : 50, #564464, \nBD Biosciences, USA) and anti-SUSD2 antibodies (Rabbit \npolyclonal, Sigma) using the Leica Bond RX system (Leica \nMicrosystems, USA) at a dilution of 1 : 100 at 4°C overnight.\nEvaluation of RON, ROR1 and SUSD2 expression  \nin stained tissues\nThe stained sections were evaluated by assessment \nof staining intensity and staining percentage. The stain-\ning intensity was divided into 0 (no stain), 1 (weak stain),  \n2 (moderate stain), and 3 (strong stain).\nThe staining distribution percentages were 0 (no stain-\ning ), 1 (1–25%), 2 (25–50%), and 3 (50–100%).\nMultiplying scores of intensity and percentage yields \nfinal stain scores from 0 to 12. We considered a score  \nof 4 as a cut point below which scores are considered low \nand above which scores are considered high to facilitate \nstatistical analysis.\nStatistical analysis\nAll statistics were performed using SPSS Statistics 22.0 for \nWindows (IBM Corp.). Continuous variables were expressed \nas the mean ±SD and median (range), and the categorical \nvariables were expressed as a number (percentage). Percent-\nages of categorical variables were compared using Pearson’s \nc\n2 test or Fisher’s exact test as appropriate. \nRecurrence free-survival (RFS) was calculated as the \ntime from surgery to date of recurrence or the most re-\ncent follow-up contact that the patient was known to be \nrecurrence free. Progression-free survival (PFS) was calcu-\nlated as the time from start of treatment to the date of \ndisease progression or the most recent follow-up contact \nthat the patient was known to be progression free. Over -\nall survival (OS) was calculated as the time from diagno-\nsis to death or the most recent follow-up contact (cen-\nsored). Stratification of RFS, PFS, distant metastasis-free \nsurvival (DMFS), and OS rates were estimated using a Ka-\nplan-Meier plot, and compared using the log-rank test. \nAll tests were two sided. A p-value < 0.05 was considered \nsignificant. \nTable 1. Association between RON, ROR1 and SUSD2 expression and histopathology\nFactor Endometrial carcinoma (N = 100) Atypical endometrial hyperplasia (N = 100) p-value*\nn % n %\nAge\n≤ 55 years 76 76 76 76 < 0.001\n> 55 years 24 24 24 24\nRON\nLow 46 46 90 90 < 0.001\nHigh 54 54 10 10\nROR1\nLow 24 42 80 80 0.001\nHigh 58 58 20 20\nSUSD2\nLow 26 26 20 20 0.005\nHigh 74 74 80 80\n* chi-square test\n\n111RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \nResults\nTable 1 shows that upregulation of RON and ROR1 and \ndown regulation of SUSD2 expression were found in endo-\nmetrial carcinoma more than atypical endometrial hyper -\nplasia (p < 0.001) (Fig. 1).\nFor RON expression in endometrial carcinoma and the \nassociation with clinicopathological parameters see Table 2  \nand Figure 2. \nHigh RON expression was significantly associated with \nlarge tumor size, high grade, presence of cervical stromal \ninvasion, presence of adnexal invasion, presence of lym-\npho-vascular invasion (p < 0.001), extent of myometrial \ninvasion (p = 0.006), parametrial invasion (p = 0.008), \nserosal invasion (p = 0.005), positive peritoneal cytology  \n(p = 0.004), presence of lymph node metastases (p = 0.003), \ndistant metastases (p = 0.009), and advanced Internatio-\nnal Federation of Gynecology and Obstetrics (FIGO) stage \n(p = 0.002).\nNo significant association was found between RON ex-\npression and age of patients (Table 3).\nFor RON expression in endometrial carcinoma and  \nthe association with prognostic and follow-up parameters \nsee Tables 4 and 5 and Figures 5 and 6.\nHigh RON expression was significantly associated with \npoor response to therapy (p = 0.046), higher incidence  \nof disease progression (p = 0.018) and higher incidence  \nof tumor recurrence (p = 0.004).\nHigh RON expression was significantly associated with \nlower RFS rate (p = 0.002), PFS rate (p = 0.008), DMFS rate \n(p = 0.019) and OS rate (p < 0.001).\nFor ROR1 expression in endometrial carcinoma and as-\nsociation with clinicopathological parameters see Table 2 \nand Figure 3. \nHigh ROR1 expression was significantly associat-\ned with older age of the patient (p  = 0.031), large tu-\nmor size (p  = 0.003), high grade (p  = 0.007), presence  \nof cervical stromal invasion, presence of adnexal invasion, \nextent of myometrial invasion, presence of lymph node \nmetastases, positive peritoneal cytology, advanced FIGO \nstage (p  < 0.001), presence of lympho-vascular invasion \n(p = 0.003), parametrial invasion (p  = 0.004), serosal in-\nvasion (p  = 0.004) and presence of distant metastases  \n(p = 0.029).\nFor ROR1 expression in endometrial carcinoma and the \nassociation with prognostic and follow-up parameters see \nTables 4 and 5 and Figures 5 and 6.\nHigh RON expression was significantly associated with \nhigher incidence of disease progression (p = 0.044) and \nunfavorable survival (p < 0.001).\nNo significant association was found between ROR1 \nexpression and poor response to therapy or tumor recur -\nrence.\nHigh ROR1 expression was significantly associated with \nlower RFS rate (p = 0.032), PFS rate (p = 0.013), DMFS rate \n(p = 0.019) and OS rate (p < 0.001).\nFor SUSD2 expression in endometrial carcinoma and \nthe association with clinicopathological parameters see \nTable 2 and Figure 4.\nLow SUSD2 expression was significantly associat-\ned with older patient age (p = 0.002), large tumor size  \n(p = 0.003), high grade (p = 0.005), presence of adnexal \ninvasion (p = 0.023), presence of lympho-vascular invasion \n(p = 0.021), extent of myometrial invasion (p = 0.002), se-\nrosal invasion (p = 0.005), presence of lymph nodes me-\ntastases (p = 0.003), distant metastases (p = 0.023), and \nadvanced FIGO stage (p = 0.011).\nA B\nC\nFig. 1. Low RON expression in endometrial hyperplasia (A), low ROR1 \nexpression in endometrial hyperplasia (B), high SUSD2 expression  \nin endometrial hyperplasia (C)\n\n112\ncontemporary oncology\nNo significant association was found between SUSD2 \nexpression and cervical stromal invasion, positive perito-\nneal cytology or parametrial invasion.\nCharacteristics EC patients (N = 100)\nn %\nAge\n≤ 55 years 76 76\n> 55 years 24 24\nSize\n< 4 cm 34 34\n> 4 cm 66 66\nGrade\nGrade I 34 34\nGrade II 36 36\nGrade III 30 30\nLVSI\nAbsent 60 60\nPresent 40 40\nExtent of myometrial invasion\n< 50% 34 34\n> 50% 66 66\nCervical stromal invasion\nAbsent 44 44\nPresent 56 56\nParametrial extension\nAbsent 84 84\nPresent 16 16\nSerosal invasion\nAbsent 64 64\nPresent 36 36\nAdnexal invasion\nAbsent 64 64\nPresent 36 36\nPeritoneal cytology\nNegative 60 60\nPositive 40 40\nLymph node\nNegative 60 60\nPositive 40 40\nDistant metastasis\nNegative 80 80\nPositive 20 20\nFIGO stage\nStage I 44 44\nStage II 20 20\nStage III 16 16\nStage IV 20 20\nTable 2. Clinicopathological and follow-up parameters, RON, ROR1 and SUSD2 expression and outcome of 100 patients with endometrial \ncarcinoma \nCharacteristics EC patients (N = 100)\nn %\nRON\nLow 44 44\nHigh 56 56\nROR1\nLow 84 42\nHigh 58 58\nSUSD2\nLow 26 26\nHigh 74 74\nTreatment\nSurgery 50 50\nConcurrent chemoradiation 30 30\nChemotherapy 20 20\nResponse to CRT (n = 50)\nOAR 28 56\nNR 22 44\nFollow-up duration (months)\nMean ±SD 36.50 ±15.77\nMedian (range) 38.50 (12–60)\nRecurrence (n = 78)\nAbsent 66 84.6\nPresent 12 15.4\nProgression (n = 56)\nAbsent 30 53.6\nPresent 26 46.4\nMetastasis (n = 40)\nAbsent 80 80\nPresent 20 20\nMortality (N = 100)\nAlive 64 64\nDied 36 36\nCRT – cardiac resynchronization therapy, EC – endometrial cancer, FIGO – Inter-\nnational Federation of Gynecology and Obstetrics, LVSI – lymph-vascular space \ninvasion, NR – non-response, OAR – organs at risk\nFor SUSD2 expression in endometrial carcinoma and \nassociation with prognostic and follow-up parameters see \nTables 4 and 5 and Figures 5 and 6.\nLow SUSD2 expression was significantly associated \nwith poor response to therapy (p = 0.005), higher inci-\ndence of disease progression (p = 0.021) and higher inci-\ndence of tumor recurrence (p = 0.023).\nLow SUSD2 expression was significantly associated \nwith lower RFS rate (p = 0.008), PFS rate (p = 0.023), and \nDMFS rate (p < 0.001).\nDiscussion\nIn the present study we assessed levels of RON at the \nprotein level using immunohistochemistry in endometrial \n\n113RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \ncarcinoma and found that RON was overexpressed in tis-\nsues and it was associated with poor clinicopathological \nparameters and unfavorable outcomes. These results were \nsimilar to results obtained by Qin et al. [9] and Zhuang  \net al. [17].\nQin et al. [9] found that high RON expression mark-\nedly increased the proliferation, migration, and invasion  \nof malignant cells, while its knockdown had the opposite \neffect; additionally, targeted therapy against RON, with the \nRON inhibitor BMS777607, antagonizes the effects of RON \noverexpression. \nAll these results collectively showed the role of RON  \nin increasing proliferation and progression of endometrial \nadenocarcinoma.\nSimilar roles of RON were found in different types  \nof cancers [18, 19].\nThe roles of RON in cancer invasion, spread and pro-\ngression are mostly due to activation of EMT , the process \nthat was incriminated in cancer progression.\nRON activation was shown to induce spindle morpholo-\ngy in tumor cells, thus facilitating invasion and spread [20].\nMoreover, RON overexpression was found to affect \nmany EMT biomarkers such as E-cadherin, which is \na marker of intercellular adhesions in epithelial cells, and \nvimentin [21]. Moreover, RON expression allows endome-\ntrial carcinoma progression and promotes deep invasion \ninto the myometrium [22].\nRON also controls vimentin expression in endometri-\nal carcinoma tissues; previous studies showed that in-\ncreased vimentin expression promotes the migration and \ninvasion of tumor cells [23]. \nSo, RON played roles in facilitating cancer invasion and \nprogression through induction of EMT of endometrial ad-\nenocarcinoma.\nAdditionally, RON could control EMT through several \npathways, such as RAS-MAPK and PI-3K-Akt pathways \n[24], and SMAD and JAK pathways [25, 26].\nBased on our results and results of previous studies, \nRON could regulate cell proliferation and EMT , which allow \ninvasion and metastases in endometrial cancer (EC) cells, \nwhich promote the development of EC. \nFor further confirmation of the role of RON in progres-\nsion of endometrial carcinoma we assessed levels of 2 oth-\ner incriminated markers of EMT in endometrial carcinoma: \nROR1 andSUSD2.\n We found that ROR1 was overexpressed in endometrial \ncarcinoma tissues and its expression was positively associ-\nated with progression and unfavorable patients’ outcome.\nFig. 2. RON expression in endometrial carcinoma (EC). High RON expression in serous EC high grade stage III 400× (A), high RON expression \nin endometroid EC high grade stage III 400× (B), low RON expression in endometroid EC low grade stage II 400× (C), negative RON expression \nin endometroid EC low grade stage I 400× (D)\nA B\nC D\n\n114\ncontemporary oncology\nTable 3. Association between RON, ROR1 and SUSD2 expression and clinicopathological features in endometrial cancer patients (N = 100)\nCharacteristics All\n(N = 100)\nRON p-value ROR1 p-value SUSD2 p-value\nLow (n = 46) High (n = 54) Low (n = 42) High (n = 58) Low (n = 26) High (n = 74)\nn % n % n % n % n % n % n %\nAge\n≤ 55 years 76 76 38 50 38 50 0.128* 38 50 38 50 0.031* 10 13.2 66 86.8 0.002*\n> 55 years 24 24 6 25 18 75 4 16.7 20 83.3 16 66.7 8 33.3\nSize\n< 4 cm 34 34 30 88.2 4 11.8 < 0.001* 30 88.2 4 11.8  0.003* 0 0 34 100 0.003*\n> 4 cm 66 66 14 21.2 52 78.8 12 18.2 54 81.8 26 39.4 40 60.6\nGrade\nGrade I 34 34 30 88.2 4 11.8 < 0.001** 30 88.2 2 11.8 0.007** 0 0 34 100 0.005**\nGrade II 36 36 12 33.3 24 66.7 12 33.3 12 66.7 10 27.8 26 72.2\nGrade III 30 30 2 6.7 28 93.3 0 0 15 100 16 53.3 28 46.7\nLVSI\nAbsent 60 60 38 63.3 22 36.7 0.005* 38 63.3 22 36.7 0.003* 10 16.7 50 83.3 0.021*\nPresent 40 40 6 15 34 85 4 10 36 90 16 40 24 60\nExtent of myometrial invasion\n< 50% 34 34 30 88.2 4 11.8 0.006* 30 88.2 4 11.8 < 0.001* 0 0 34 100 0.002*\n> 50% 66 66 14 21.2 52 78.8 12 18.2 54 81.8 26 39.4 40 60.6\nCervical stromal invasion\nAbsent 44 44 34 77.3 10 22.7 < 0.001* 34 77.3 10 22.7 < 0.001* 8 18.2 36 81.8 0.264*\nPresent 56 56 10 17.9 46 82.1 8 14.3 48 85.7 18 32.1 38 67.9\nParametrial extension\nAbsent 84 84 48 59.4 36 40.6 0.008* 48 59.4 36 40.6 0.004* 22 18.8 62 81.2 0.180*\nPresent 16 16 6 16.7 10 83.3 4 11.1 12 88.9  4 38.9 12 61.1\nSerosal invasion\nAbsent 64 64 38 59.4 26 40.6 0.005* 38 59.4 26 40.6 0.002* 12 18.8 52 81.2 0.018*\nPresent 36 36 6 16.7 30 83.3 4 11.1 32 88.9 14 38.9 22 61.1\nAdnexal invasion\nAbsent 64 64 42 65.6 22 34.4 < 0.001* 42 65.6 22 34.4 < 0.001* 10 15.6 54 84.4 0.023*\nPresent 36 36 2 5.6 34 94.4 0 0 36 100 16 44.4 20 55.6\nPeritoneal cytology\nNegative 60 60 38 63.3 22 36.7 0.004* 38 63.3 22 36.7 < 0.001* 10 16.7 50 83.3 0.065*\nPositive 40 40 6 15 34 85 4 10 36 90 16 40 24 60\n\n115RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \nCharacteristics All\n(N = 100)\nRON p-value ROR1 p-value SUSD2 p-value\nLow (n = 46) High (n = 54) Low (n = 42) High (n = 58) Low (n = 26) High (n = 74)\nn % n % n % n % n % n % n %\nLymph node\nNegative 60 60 38 63.3 22 36.7 0.003* 38 63.3 22 36.7 < 0.001* 10 16.7 50 83.3 0.003*\nPositive 40 40 6 15 34 85 4 10 36 90 16 40 24 60\nDistant metastasis\nNegative 80 80 42 52.2 38 47.5 0.009* 42 52.5 38 47.5 0.029* 16 20 64 80 0.023*\nPositive 20 20 2 10 18 90 0 0 20 100 10 50 10 50\nFIGO stage\nStage I 44 44 34 77.3 10 22.7  0.002** 34 77.3 10 22.7 < 0.001** 6 13.6 38 86.4 0.011**\nStage II 20 20 4 20 16 80 4 20 16 80 4 20 16 80\nStage III 16 16 4 25 12 75 4 25 12 75 6 37.5 10 62.5\nStage IV 20 20 4 10 18 90 2 10 18 90 10 50 10 50\nFIGO – International Federation of Gynecology and Obstetrics, LVSI – lymph-vascular space invasion\n* chi-square test, ** chi-square test for trend\nTable 3. Cont.\nTable 4. Association between RON, ROR1 and SUSD2 expression and patients’ outcome in endometrial cancer patients (N = 100)\nOutcome All RON p-value* ROR1 p-value* SUSD2 p-value*\nLow High Low High Low High\nNo. % No. % No. % n % n % n % n %\nResponse to CRT (N = 50) (N = 10) (N = 40) (N = 8) (N = 42) (N = 26) (N = 24)\nOAR 28 56 10 100 18 45 0.046 8 100 20 47 0.105 18 69.2 10 41.7 0.005\nNR 22 44 0 0 22 55 0 0 22 52. 8 30.8 14 58.3\nRecurrence (N = 78) (N = 44) (N = 34) (N = 42) (N = 36) (N = 18) (N = 60)\nAbsent 66 84.6 44 100 22 64.7 0.004 40 95.2 26 72.2 0.077 12 66.7 54 90 0.023\nPresent 12 15.4 0 0 12 35.3 2 4.8 10 27.8 6 33.3 6 10\nProgression (N = 56) (N = 12) (N = 44) (N = 10) (N = 46) (N = 26) (N = 30)\nAbsent 30 53.6 12 100 18 40.9 0.018 10 100 20 43.5 0.044 20 76.9 5 33.3 0.021\nPresent 26 46.4 0 0 26 59.1 0 0 26 56.5 6 23.1 10 66.7\nMetastasis (N = 80) (N = 42) (N = 38) (N = 42) (N = 38) (N = 16) (N = 64)\nAbsent 64 80 38 90.5 26 68.4 0.120 38 90.5 26 68.4 0.120 6 37.5 58 90.6 0.004\nPresent 16 20 4 9.5 12 31.6 4 9.5 12 31.6 10 62.5 6 9.4\nMortality (N = 100) (N = 44) (N = 56) (N = 42) (N = 62) (N = 26) (N = 74)\nAlive 64 64 40 90.9 24 42.9 < 0.001 38 90.5 26 44.8 0.001 14 53.8 50 67.6 0.504\nDied 36 36 4 9.1 32 57.1 4 9.5 36 55.2 12 46.2 24 32.4\nCRT – cardiac resynchronization therapy, NR – non-response, OAR – organs at risk\n* chi-square test\n\n116\ncontemporary oncologyTable 5. Association between RON, ROR1 and SUSD2 expression and survival rates in endometrial cancer patients (N = 100)\nOutcome All RON p-value* ROR1 p-value* SUSD2 p-value*\nLow High Low High Low High\nRFS (N = 78) (n = 44) (n = 34) (n = 42) (n = 36) (n = 18) (n = 40)\nMean (months)\n(95% CI)\n54.31 \n(50–58.62)\n45.90\n(41.29–50.51)\n32.76\n(24.74–40.78)\n0.002 59\n(57.14–60.85)\n44.65\n(37.44–51.85)\n0.032 29.30\n(24.13–34.47)\n57.02\n(53.53–60.52)\n0.008\n1 year RFS (%) 97.4 100 94.1 100 94.4 100 96.7\n2 year RFS (%) 89.6 100 76.5 100 77 63.5 96.7\n3 year RFS (%) 89.6 100 76.5 100 77 – 96.7\n4 year RFS (%) 84.9 100 65.5 100 66 – 91.6\n5 year RFS (%) 79.2 – – 90 – – 85.5\nPFS (N = 56) (n = 12) (n = 44) (n = 10) (n = 46) (n = 26) (n = 30)\nMean (months)\n(95% CI)\n32.11 \n(23.96–40.26)\n37.67 \n(25.29–50.04)\n17.54 \n(12.42–22.66)\n0.008 41.20 \n(30.08–52.31)\n17.65 \n(12.77–22.53)\n0.013 31.23\n(27.35–35.10)\n23.40\n(12.53–34.26)\n0.023\n1 year PFS (%) 64.3 100 54.5 100 56.5 92.3 40\n2 year PFS (%) 64.3 100 54.5 100 56.5 92.3 40\n3 year PFS (%) 64.3 100 21.8 100 22.6 55.4 32\n4 year PFS (%) 45 – 21.8 – 22.6 – 32\n5 year PFS(%) – – – – – – –\nDMFS (N = 80) (n = 42) (n = 38) (n = 42) (n = 38) (n = 16) (n = 64)\nMean (months)\n(95% CI)\n52.26 \n(47.38–57.14)\n57.38 \n(53.91–60.84)\n41.61 \n(33.63–49.59)\n0.019 57.38 \n(53.91–60.84)\n41.61 \n(33.63–49.59)\n0.019 30.55\n(24.80–36.29)\n55.89\n(51.41–60.37)\n< 0.001\n1 year DMFS (%) 97.4 100 94.1 100 94.1 87.5 100\n2 year DMFS (%) 92.1 100 82.4 100 82.4 87.5 93.3\n3 year DMFS (%) 77.4 90.5 74.9 90.5 58.2 – 89.9\n4 year DMFS (%) 77.4 90.5 58.2 90.5 58.2 – 89.9\n5 year DMFS (%) 77.4 90.5 – 90.5 – – 89.9\nOS (N = 100) (n = 44) (n = 56) (n = 42) (n = 58) (n = 26) (n = 74)\nMean (months)\n(95% CI)\n46.13 \n(40.82–51.45)\n57.61 \n(54.48–60.75)\n34.18 \n(27.40–40.96)\n< 0.001 57.61 \n(54.48–60.75)\n34.63 \n(27.94–41.32)\n< 0.001 32.86 \n(28.61–37.11)\n47.41 \n(41.16–53.67)\n0.070\n1 year OS (%) 88 100 78.6 100 79.3 92.3 86.5\n2 year OS (%) 79.3 100 61.2 100 62.8 92.3 75.5\n3 year OS (%) 66.9 90.5 44.5 90.5 45.6 18.5 72.7\n4 year OS (%) 64.4 90.5 39 90.5 39.9 – 72.7\n5 year OS (%) 56.8 90.5 – 90.5 – – 64.1\nDMFS – distant metastasis-free survival, OS – overall survival, PFS – progression-free survival, RFS – recurrence-free survival\n* log rank test\n\n117RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \nA B\nC D\nFig. 3. ROR1 expression in endometrial carcinoma (EC). High ROR1 expression in serous EC high grade stage III 400× (A), high ROR1 expres-\nsion in endometroid EC high grade stage III 400× (B), low ROR1 expression in endometroid EC low grade stage II 400× (C), negative ROR1 \nexpression in endometroid EC low grade stage I 400× (D)\nSimilar results were reported by Liu et al. [14] and Henry \net al. [27], who confirmed the role of ROR1 as a novel prog-\nnostic marker and therapeutic target in EC. \nWe observed that patients with high expression  \nof ROR1 had lower OS and PFS rates in comparison with \npatients with low ROR1 expression levels. \nWe found an association between ROR1 expression and \nhigher grade and advanced stage of endometrial carcino-\nma, which was similar to the results of Liu et al. [14] and \nthose of Zhang et al. [28] in ovarian and pancreatic cancer.\nROR1 was found to play a role in cancer progression \nthrough activation of EMT through activation of Wnt sig-\nnaling [29, 30], which was proved to be associated with \nmetastasis in ovarian cancer [31].\nPrevious studies showed that ROR1 played an import-\nant role in the EMT process, which has a critical role in con-\ntrolling cancer metastases [32, 33].\nRegarding the association between ROR1 expression \nand survival rates, it was found that ROR1 overexpression \nwas related to unfavorable survival rates and it could be \nconsidered a promising novel therapeutic target for recent \nmanagement of EC. \nThe recently detected ROR1 inhibitor cirmtuzumab is \na monoclonal antibody that has proven to be effective  \nin inhibiting ROR1 signaling in ovarian cancer and chronic \nlymphocytic leukemia (CLL) [34, 35].\nAnother ROR1-targeting therapy which is called ROR1 \nchimeric antigen receptor T cell therapy, as described  \nby Berger et al. [36], was tried as targeted therapy in CLL \nand triple negative breast carcinoma.\nThese new ROR1 inhibitors and targeted therapies \ncould be beneficial to EC patients, particularly those with \nhigh expression of ROR1.\nOur study confirms the prognostic role of ROR1 in en-\ndometrial carcinoma progression and points to the future \nbenefits of ROR1-targeting therapies in EC patients. \nWe observed a positive association between RON and \nROR1 expression in tissues of endometrial carcinoma; \nboth biomarkers performed their work through activation \nof EMT and both are associated with cancer progression \nand unfavorable outcomes.\nWe assessed expression of another marker, SUSD2, \nwhich has variable prognostic roles in different cancer \ntypes.\nSeveral studies have assessed associations between \nSUSD2 expression and prognosis of many cancers, e.g. \nbreast, colon [16, 37], but its role in endometrial carcinoma \nhas not been clarified yet.\n\n118\ncontemporary oncology\nOur study demonstrated that tissue protein expression \nof SUSD2 was downregulated in endometrial carcinoma \ntissues, its low expression was related to unfavorable \nprognostic and clinicopathological parameters and its ex-\npression was inversely associated with RON and ROR1 ex-\npression in tissues of endometrial carcinoma.\nSimilar results were obtained in hepatocellular carcino-\nma tissues in the study of Liu et al. [38], which showed \nthat SUSD2 expression was reduced in malignant tissues \nmore than adjacent non-neoplastic tissues, suggesting \nthat SUSD2 down-regulation plays important roles in car -\ncinogenesis and cancer progression. \nA possible explanation of our results is that SUSD2 \ndownregulation led to an increased rate of cell prolifera-\ntion and reduced apoptosis; thus, SUSD2 had a tumor sup-\npressor role and inhibited tumor growth [38].\nAdditionally we observed that high levels of SUSD2 \nmarkedly reduced invasiveness and migration ability of \nendometrial carcinoma cells, and we found that it was in-\nversely associated with the EMT markers ROR1 and RON1.\nMoreover, we found that high levels of SUSD2 expres-\nsion in the tumor were associated with improved patient \nsurvival, which points to the tumor suppressor role of \nSUSD2. Similar results were obtained in serous ovarian \ncarcinoma by Sheets et al. [39, 40], who reported that high \nSUSD2 expression could inhibit ovarian carcinoma metas-\ntasis. \nDifferent results from ours were obtained in some stud-\nies on different cancer types.\nZhang et al. [41] reported that SUSD2 expression is up-\nregulated in EC cells, associated with unfavorable progno-\nsis, and its downregulation improves patients’ prognosis. \nAdditionally they concluded that SUSD2 could be consid-\nered a chemotherapeutic target in EC. Their explanation \nfor their results was that SUSD2 participates in apoptosis \nand cell senescence in EC cells and thus affects invasive-\nness and spread.\nAlso the results of Xu et al. [42] showed that high ex-\npression of SUSD2 increased ovarian cancer metastasis. \nThose contrasting results could be explained by differ -\nences in methods of tissue expression, subcellular local-\nization of SUSD2 and different metastasis mechanisms \n[43, 44]. Also the results of Watson et al. [16] showed that \nhigh SUSD2 expression in breast cancer enhanced cancer \ncell invasion and metastases. \nConclusions\nWe conclude that upregulation of RON and ROR1 in ad-\ndition to downregulation of SUSD2 might be considered \nA B\nC D\nFig. 4. SUSD2 expression in endometrial carcinoma (EC). High SUSD2 expression in endometroid EC low grade stage I 400× (A), high SUSD2 \nexpression in endometroid EC low grade stage II 400× (B), low SUSD2 expression in serous EC high grade stage III 200× (C), low SUSD2 \nexpression in serous EC high grade stage III 400 × (D)\n\n119RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \nA\nC\nB\nD\nCum survival Cum survival \nCum survival Cum survival \n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\nFig. 5. Five-year disease-free survival (DFS) rate of included patients with endometrial carcinoma (A), DFS rate in association with RON ex-\npression (B), DFS rate in association with RON and ROR1 expression (C), DFS rate in association with SUSD2 expression (D)\nDFS – disease-free survival\nSurvival function\nSurvival function\nSurvival function\nSurvival function\n 0 10 20 30 40 50 60\nDFS [months]\n Survival function         Censored\n 0 10 20 30 40 50 60\nDFS [months]\nROR1      Low        High        Low-censored        High-censored \n 0 10 20 30 40 50 60\nDFS [months]\nRON      Low        High        Low-censored        High-censored \n 0 10 20 30 40 50 60\nDFS [months]\nSUSD2      Low       High       Low-censored       High-censored \n\n120\ncontemporary oncology\nA\nC\nB\nD\nCum survival Cum survival \nCum survival Cum survival \n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\n1.0\n0.8\n0.6\n0.4\n0.2\n0\nFig. 6. Five-year overall survival (OS) rate of included patients with endometrial carcinoma (A), OS rate in association with RON expression (B),  \nOS rate in association with RON and ROR1 expression (C), OS rate in association with SUSD2 expression (D)\nOS – overall survival\nSurvival function\nSurvival function\nSurvival function\nSurvival function\n 0 10 20 30 40 50 60\nOS (months)\n Survival function         Censored\n 0 10 20 30 40 50 60\nOS (months)\nROR1      Low        High        Low-censored        High-censored \n 0 10 20 30 40 50 60\nOS (months)\nRON      Low        High        Low-censored        High-censored \n 0 10 20 30 40 50 60\nOS (months)\nSUSD2      Low       High       Low-censored       High-censored \n\n121RON, ROR1 and SUSD2 expression in tissues of endometrial carcinoma patients. Clinicopathological and prognostic implications \na promoting factor for EC cells’ proliferation, migration, \nEMT , and invasion.\nRecommendations\nWe recommend performing further studies on gene \nexpression of studied markers, aiming at their appraisal \nas novel therapeutic targets for treatment of endometri-\nal adenocarcinoma.\nMoreover, we recommend assessing markers’ ex-\npression in different variants of endometrial carcinoma \nin the recent molecular classification of endometrial \ncancer, to detect their roles.\nPre-operative detection of glandular cells (GC) in cer-\nvical smear analysis might be a predictor for endometri-\nal cancer local recurrence [45]. Relative telomere length \n(RTL) in cell-free DNA (cfDNA) for EC, and cfDNA RTL \nanalysis might be a potential diagnostic tool for early EC \ndetection, progression, staging, and grading. \nHowever, further studies are needed to confirm these \nresults focusing on high-risk patients who might benefit \nfrom this tool, as TL shortening is not specific for EC [46].\nWe recommend investigating correlations between \nstudied markers’ expression, pre-operative detection of \nGC in cervical-smear analysis and cfDNA RTL analysis for \nearly detection of endometrial cancer recurrence.\nThe authors declare no conflict of interest.\nReferences\n1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: Can-\ncer J Clin 2013; 63: 11-30. \n2. Lortet-Tieulent J, Ferlay J, Bray F , Jemal. International patterns and \ntrends in endometrial cancer incidence, 1978–2013. JNCI J Natl \nCancer Inst 2017; 110: 354-361.\n3. Makker A, Goel MM. 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Shield K, Ackland ML, Ahmed N, Rice GE. Multicellular spheroids in \novarian cancer metastases: biology and pathology. Gynecol Oncol \n2009; 113: 143-148. \n44. Naora H, Montell DJ. Ovarian cancer metastasis: integrating in-\nsights from disparate model organisms. Nat Rev Cancer 2005;  \n5: 355-366. \n45. Casarin J, Bogani G, Serati M, et al. Presence of glandular cells at \nthe preoperative cervical cytology and local recurrence in endome-\ntrial cancer. Int J Gynecol Pathol 2020; 39: 522-528.\n46. Benati M, Montagnana M, Danese E, et al., Aberrant telomere \nlength in circulating cell-free DNA as possible blood biomarker \nwith high diagnostic performance in endometrial cancer. Pathol \nOncol Res 2020; 26: 2281-2289.\nAddress for correspondence\nRanda Mohamed Kaf, MD\nPathology Department\nFaculty of Medicine\nZagazig University\nZagazig, Egypt\ne-mail: loayelhady@gmail.com\nSubmitted:  07.03.2022\nAccepted:  22.05.2022","source_license":"CC0","license_restricted":false}