Abstract
Endometrial cancer is one of the most common gynecologic malignancies worldwide. Only two agents have been approved by Food and Drug Administration for endometrial cancer since 1971. There is a need to identify molecular targets to treat advanced endometrial cancer. The receptor for hyaluronan-mediated motility (RHAMM) is upregulated in various types of cancer. Here, we aimed to determine the clinical significance of RHAMM expression in endometrial cancer. Two hundred and twenty-five cases of endometrial cancer, including serous and endometrioid types, and 8 cases of normal endometrium were used for studying RHAMM protein levels. Publically available The Cancer Genome Atlas (TCGA) database was also queried for RHAMM mRNA expression in endometrial cancer. Increased expression of RHAMM protein was seen in endometrial cancer compared with no or weak expression in normal endometrium. RHAMM expression positively correlated with tumor grade. RHAMM expression was significantly increased in endometrial serous carcinomas, which are high-grade, aggressive types of endometrial cancer, compared with the relatively less aggressive endometrioid carcinomas. RHAMM expression also correlated with the presence of lymphovascular invasion. RHAMM mRNA expression correlated with decreased survival in the TCGA cohort. Therefore, increased RHAMM expression in endometrial cancer is associated with high-grade tumors and is indicative of more aggressive behavior. These findings suggest RHAMM as a prognostic factor in endometrial cancer and as a potential therapeutic target in advanced endometrial cancer for future studies.
Keywords: RHAMM, endometrial cancer, serous, prognosis, tumor progression
Introduction
Endometrial cancer is the most common gynecologic malignancies in the United States, and accounts for a worldwide cancer incidence and mortality of approximately 5% and 2%, respectively (1). It is the sixth most common cancer and the 14th leading cause of death with 320,000 estimated new cases and 76,000 deaths worldwide in 2012 (2). Endometrial cancer incidence rates have increased in recent years in multiple countries with the highest rates seen in North America and Eastern and Northern Europe (3). The estimated number of new cases of endometrial cancer in the United States in 2018 is 63,230 with an estimated 11,350 deaths. Prognosis and survival for women with endometrial cancer, like many other cancers, is largely dependent on tumor stage at diagnosis. The five-year survival rate is 95% for women with localized disease confined to the uterus, which then drops to 69% when it has spread to the lymph nodes and drops significantly to 16% for those with distant metastasis. Death rates for endometrial cancer rose by approximately 2% per year from 2011 to 2015 in contrast to the declining overall cancer death rates in women during this same time period (4). Notably, cancer survival in women has improved for the most common cancers except for endometrial cancer, among a few others (5).
Currently endometrial cancer diagnosis is based on the morphologic light microscopic findings. The most common histologic types of endometrial cancer are endometrioid and serous carcinoma with endometrioid carcinoma representing approximately 80–85% and serous approximately 10% of all endometrial cancer. Traditionally, endometrial cancer can be categorized as type I or type II on the basis of clinical, endocrine, and epidemiologic characteristics (6). However, more recent genomic studies from the TCGA have classified endometrial cancer into 4 molecular subtypes. Endometrioid carcinoma is the prototype type I carcinoma with the vast majority falling into 3 of the molecular subtypes and are indolent tumors with a good prognosis. In contrast, serous carcinoma is the prototype type II carcinoma, is highly aggressive and constitutes the majority of one of the molecular subtypes. Although it represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer (7).
The treatment for endometrial cancer depends largely on surgical stage at presentation. About 75% of patients with endometrial cancer are diagnosed in the early stages with localized disease, FIGO stage I or II, and can be cured by surgical excision alone (8). Patients with additional advanced risk factors, including lymphovascular invasion (LVI) and greater than 50% myometrial invasion, are also treated with adjuvant radiation therapy, which has been shown to reduce local recurrence but does not affect overall 5-year survival. Conversely, 10–15% of patients with endometrial cancer are diagnosed in the advanced stages with extra-uterine disease, FIGO stage III or IV, which accounts for over 50% of uterine cancer-related deaths. Patients with advanced stage disease are often considered as a single group for investigational and treatment purposes; however, they represent heterogeneous disease with varying tumor types and different prognoses. Treatment for advanced endometrial cancer generally consists of a multimodal approach including surgery, chemotherapy, and radiation therapy (9,10). Many treatments, including radiation therapy for high-risk, low-stage cancers and certain chemotherapy regimens for advanced cancers, decrease local recurrence or increase therapeutic response but do not affect overall survival, and ultimately many patients succumb to metastatic disease. Hence, there is an urgent need to develop better therapeutic regimens.
The receptor for hyaluronic acid mediated motility (RHAMM), also known as HMMR/CD168/IHABP, is a protein with multiple cellular functions. It was first identified as a soluble binding partner of the extracellular matrix component hyaluronic acid (HA) in the secretion product of fibroblasts. It plays a role in response to tissue injury and wound repair (11,12). It also contributes to cell-cycle progression through involvement with microtubule spindle formation and activates cell signaling pathways that promote migration (13).
RHAMM protein expression is restricted to certain normal tissues, specifically in tissues with an inherently high turnover such as thymus, lymph node, tonsil, bone marrow, germ cells of the adult testes, and the regenerative zones of the intestinal epithelium and skin (14). On the other hand, RHAMM is expressed in multiple tumor types, and increased expression is associated with tumor migration, invasiveness and progression, as well as adverse prognosis (14–17). It has recently been shown, using immunohistochemistry (IHC), that RHAMM is expressed in ovarian carcinoma, and that the increased expression is strongly correlated with high-grade tumors and advanced stage (18). It has also been showed that RHAMM protein expression correlates with histologic tumor grade in endometrioid carcinoma (19,20). However, the expression of RHAMM in serous carcinoma and its possible clinical impact has not been studied. In this study, we aimed to determine RHAMM expression in endometrioid and serous types of endometrial cancer, and to correlate RHAMM expression with various tumor-related parameters, including tumor grade, depth of invasion, LVI, and the presence of metastasis.
Materials and Methods
Clinical Specimens
The study was approved by the New York Presbyterian Hospital/Weill Cornell Medicine Institutional Review Board. Patient tissues from endometrial biopsies or hysterectomy specimens were collected from women diagnosed with endometrial cancer. The tissue examined included only primary endometrial cancer. All tissue specimens were fixed with 10% formalin, paraffin-embedded, sectioned, and stained with hematoxylin and eosin (H&E). Two tissue microarrays (TMAs) were constructed in-house from a cohort of 191 cases of endometrial cancer consisting of 44 serous cases and 147 endometrioid cases including 69 FIGO grade 1, 63 FIGO grade 2, and 15 FIGO grade 3, resected at New York-Presbyterian Hospital/Weill Cornell Medicine. The TMAs were constructed using tissue cores of 0.6 mm diameter, and each tumor was represented by three cores punched from morphologically representative tumor areas after histology review. An additional 34 cases of serous carcinomas were evaluated using whole slide sections. Benign proliferative and secretory endometrium was incorporated into each TMA as controls.
Immunohistochemical Analysis of RHAMM Staining
Immunohistochemical analysis was performed using a rabbit recombinant monoclonal RHAMM antibody [EPR4055] (Abcam, Cambridge, MA) on a Leica Bond system (Buffalo Grove, IL) following the manufacturer’s protocol. The sections were pre-treated using heat mediated antigen retrieval with Tris-EDTA buffer (pH = 9, epitope retrieval solution 2) for 20 min and incubated with RHAMM antibody (1:100 dilution) for 15 min at room temperature. RHAMM was detected using an HRP conjugated compact polymer system and DAB as the chromogen. Each section was counterstained with hematoxylin and mounted with Leica Micromount. Immunostaining of RHAMM was scored based on average percentage of positive tumor cells (0, <1%; 1+, 1–5%; 2+, 5–20%; 3+, >20%).
Statistical Analysis
The Cochran-Mantel-Haenszel statistic was used to test a linear trend between ordinal clinical features and the expression of RHAMM protein. The test is two-sided with an alpha of 0.05 as the cutoff for statistical significance. All analyses were performed in SAS9.4 (SAS Institute, Cary, NC).
TCGA datasets with RNA-Seq version 2 gene expression values including normalized gene and isoform values, and clinical data from uterine corpus endometrial cancer were directly downloaded from http://cancergenome.nih.gov/ and analyzed using statistical programing software R (version 3.4.3) or statistical software Prism (version 7.0a). Mann-Whitney U test was used to compare expression differences between two groups selected. Kaplan-Meier method was used to estimate the survival probability followed by a log-rank test to compare group differences. P value < 0.05 is considered as statistical significance. Isoform 1: uc003lzh or NM_001142556. Isoform2 (RHAMMA): uc003lzf or NM_012484. Isoform 3 (RHAMMB): uc003lzg, or NM_012485. Isoform 4: uc011dem or NM_001142557.
Results
Clinical features
A total of 225 cases of endometrial cancer were evaluated for the expression of RHAMM using immunohistochemistry. The specificity of the RHAMM antibody used in this study has been verified by showing reduction of RHAMM protein levels in shRNA RHAMM knockdown tumor cells (21). The subtypes of endometrial cancer included 78 serous carcinomas and 147 endometrioid carcinomas, the latter consisting of 69 well differentiated (FIGO grade 1), 63 moderately differentiated (FIGO grade 2), and 15 poorly differentiated (FIGO grade 3) cases. RHAMM expression by IHC was negative (0) in 62 (28%), weak (1+) in 109 (48%), moderate in 32 (14%) and strong (3+) in 22 (10%) cases (Table 1). Normal proliferative or secretory endometrium showed either no (0) [3/8, 37%] or weak (1+) [5/8, 63%] RHAMM expression.
Table 1:
Clinical characteristics of RHAMM in endometrial cancer cases
| RHAMM | |||||||
|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | ||||
| Variable | Total | P 1 | |||||
| Tumor Grade, [n (%)] | |||||||
| 1 | 69 (30.7) | 34 (54.8) | 31 (28.4) | 4 (12.5) | 0 (0.0) | <.001 | [Tr] |
| 2 | 63 (28.0) | 15 (24.2) | 39 (35.8) | 9 (28.1) | 0 (0.0) | ||
| 3 | 93 (41.3) | 13 (21.0) | 39 (35.8) | 19 (59.4) | 22 (100) | ||
| Tumor Type, [n (%)] | |||||||
| Endometrioid | 147 (65.3) | 53 (85.5) | 78 (71.6) | 16 (50.0) | 0 (0.0) | <.001 | [Tr] |
| Serous | 78 (34.7) | 9 (14.5) | 31 (28.4) | 16 (50.0) | 22 (100) | ||
| Depth, [n (%)] | |||||||
| No invasion | 41 (19.6) | 12 (19.4) | 24 (22.2) | 3 (10.3) | 2 (20.0) | 0.680 | [Tr] |
| <50% invasion | 110 (52.6) | 30 (48.4) | 58 (53.7) | 18 (62.1) | 4 (40.0) | ||
| >50% invasion | 49 (23.4) | 19 (30.6) | 20 (18.5) | 6 (20.7) | 4 (40.0) | ||
| Surface involvement | 9 (4.3) | 1 (1.6) | 6 (5.6) | 2 (6.9) | 0 (0.0) | ||
| LVI, [n (%)] | |||||||
| Absent | 146 (70.2) | 47 (79.7) | 76 (73.1) | 14 (50.0) | 9 (52.9) | 0.003 | [Tr] |
| Present | 62 (29.8) | 12 (20.3) | 28 (26.9) | 14 (50.0) | 8 (47.1) | ||
| Met, [n (%)] | |||||||
| Absent | 176 (81.5) | 53 (85.5) | 89 (82.4) | 23 (79.3) | 11 (64.7) | 0.073 | [Tr] |
| Present | 40 (18.5) | 9 (14.5) | 19 (17.6) | 6 (20.7) | 6 (35.3) | ||
Correlation of RHAMM expression with tumor type, grade, and progression
RHAMM expression was significantly increased in serous carcinomas compared with endometrioid tumors (P < 0.001). Specifically, all 22 cases with strong (3+) RHAMM expression were serous carcinomas (Table 1). There was also a highly significant increase in RHAMM expression with increasing grade of the tumor across all tumor types (P < 0.001). Increased expression of RHAMM was also independently associated with the presence of LVI (P = 0.003). No significant correlation was identified with RHAMM expression and the depth of invasion (Table 1). RHAMM protein expression in the primary endometrial cancer and the presence of metastatic tumors showed a trend toward statistical significance (Table 1, P = 0.073).
As a result of our observation that RHAMM expression was significantly different between serous and non-serous, endometrioid carcinomas, we decided to investigate whether the correlation between RHAMM expression and tumor grade and stage parameters differs in these two histologic subtypes. The majority of non-serous, endometrioid carcinomas had no (0) or weak (1+) RHAMM expression. Specifically, 53 of 147 (36%) were negative (0), 78 (53%) were weak (1+), and 16 (11%) were moderate (2+). There were no endometrioid carcinomas with strong (3+) RHAMM expression. RHAMM expression in endometrioid carcinomas correlated with tumor grade (P = 0.003) and showed a trend towards a correlation with the presence of LVI (P = 0.053) (Table 2). However, no significant correlation was identified between RHAMM expression and depth of myometrial invasion or the presence of metastasis (Table 2).
Table 2:
Clinical characteristics of RHAMM in endometrioid-type carcinoma cases
| RHAMM | ||||||
|---|---|---|---|---|---|---|
| 0 | 1 | 2 | ||||
| Variable | Total | P 1 | ||||
| Tumor Grade, [n (%)] | ||||||
| 1 | 69 (46.9) | 34 (64.2) | 31 (39.7) | 4 (25.0) | 0.003 | [Tr] |
| 2 | 63 (42.9) | 15 (28.3) | 39 (50.0) | 9 (56.3) | ||
| 3 | 15 (10.2) | 4 (7.5) | 8 (10.3) | 3 (18.8) | ||
| Depth, [n (%)] | ||||||
| No invasion | 27 (18.4) | 9 (17.0) | 18 (23.1) | 0 (0.0) | 0.677 | [Tr] |
| <50% invasion | 85 (57.8) | 27 (50.9) | 46 (59.0) | 12 (75.0) | ||
| >50% invasion | 32 (21.8) | 16 (30.2) | 12 (15.4) | 4 (25.0) | ||
| Surface involvement | 3 (2.0) | 1 (1.9) | 2 (2.6) | 0 (0.0) | ||
| LVI, [n (%)] | ||||||
| Absent | 110 (77.5) | 43 (84.3) | 58 (76.3) | 9 (60.0) | 0.053 | [Tr] |
| Present | 32 (22.5) | 8 (15.7) | 18 (23.7) | 6 (40.0) | ||
| Met, [n (%)] | ||||||
| Absent | 130 (88.4) | 47 (88.7) | 70 (89.7) | 13 (81.3) | 0.606 | [Tr] |
| Present | 17 (11.6) | 6 (11.3) | 8 (10.3) | 3 (18.8) | ||
In contrast to endometrioid carcinomas, nearly half of the serous carcinomas had moderate (2+) or strong (3+) RHAMM expression. Specifically, 9 of 78 (12%) were negative (0), 31 (40%) were weak (1+), 16 (21%) were moderate (2+), and 22 (28%) were strong (3+). RHAMM expression had no correlation with individual stage parameters including depth of invasion or LVI in serous carcinomas (Table 3).
Table 3:
Clinical characteristics of RHAMM in serous-type carcinoma cases
| RHAMM | |||||||
|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | ||||
| Variable | Total | P 1 | |||||
| Depth, [n (%)] | |||||||
| No invasion | 14 (22.6) | 3 (33.3) | 6 (20.0) | 3 (23.1) | 2 (20.0) | 0.858 | [Tr] |
| <50% invasion | 25 (40.3) | 3 (33.3) | 12 (40.0) | 6 (46.2) | 4 (40.0) | ||
| >50% invasion | 17 (27.4) | 3 (33.3) | 8 (26.7) | 2 (15.4) | 4 (40.0) | ||
| Surface Involvement | 6 (9.7) | 0 (0.0) | 4 (13.3) | 2 (15.4) | 0 (0.0) | ||
| LVI, [n (%)] | |||||||
| Absent | 36 (54.5) | 4 (50.0) | 18 (64.3) | 5 (38.5) | 9 (52.9) | 0.577 | [Tr] |
| Present | 30 (45.5) | 4 (50.0) | 10 (35.7) | 8 (61.5) | 8 (47.1) | ||
| Met, [n (%)] | |||||||
| Absent | 46 (66.7) | 6 (66.7) | 19 (63.3) | 10 (76.9) | 11 (64.7) | 0.866 | [Tr] |
| Present | 23 (33.3) | 3 (33.3) | 11 (36.7) | 3 (23.1) | 6 (35.3) | ||
RHAMM expression and prognostic significance in TCGA endometrial cancer cohort
To determine whether RHAMM mRNA expression levels in endometrial cancer are also upregulated, we queried The Cancer Genome Atlas (TCGA) database for endometrial cancer datasets. RHAMM gene expression was significantly higher in endometrial cancer (365 cases) than in normal endometrial tissue (11 cases) (P < 0.0001, Figure 2A). The average RHAMM mRNA expression was 16-fold higher in endometrial cancer than in normal tissue. Survival analysis based on mRNA expression levels showed that higher RHAMM expression predicts poor outcomes in these 365 cases of endometrial cancer (P < 0.05, Figure 2B).
Figure 2. RHAMM gene expression is associated with poor prognosis.
(A) The relative expression RHAMM RNA-Seq version 2 values from 365 cases of endometrial cancer and 11 normal control tissues of TCGA dataset are plotted. (B) Upregulation of RHAMM is associated with poor prognosis of the TCGA cohort (50% quartile (median); RHAMM low, n =183; RHAMM high, n =182). (C) The means and standard errors of 4 variants of RHAMM expression values from TCGA endometrial cancer and normal tissues are plotted for comparison. (D) The means and standard errors of 4 variants of RHAMM expression values from 2 subtypes of endometrial cancer are plotted for comparison. *: P < 0.05; **: P < 0.01; ****: P < 0.0001.
The RHAMM gene encodes 18 exons and 4 unique variants are generated through alternative splicing (RHAMMv1 to RHAMMv4, UCSC genome browser GRCh37/hg19 Assembly). We analyzed the transcript levels of the 4 RHAMM variants in normal endometrial tissues and endometrial cancer from TCGA. Transcript levels of RHAMMv1, RHAMMv3 (RHAMMB), and RHAMMv4 were significantly higher in cancers compared with normal tissues (Figure 2C). Furthermore, we analyzed the transcript levels of the 4 RHAMM variants in endometrioid-type endometrial carcinomas and serous endometrial carcinomas. RHAMMv1 did not express differently in these 2 subtypes of carcinomas. In contrast, both RHAMMv3 (RHAMMB) and RHAMMv4 showed significantly higher expression in serous endometrial carcinomas than in endometrioid carcinomas (Figure 2D, P < 0.01 and P < 0.05), respectively.
Discussion
We and others have shown that RHAMM mRNA and protein expression peaks at cell cycle G2/M phase and that RHAMM is located on mitotic spindles in anaphase and metaphase (14,22–25). It has been recently shown that RHAMM functions in the spindle positioning pathway and chromosome segregation (26,27). For these reasons, we expect the levels of RHAMM expression to reflect the proportion of endometrial cancer cells in active cell cycle and not in resting state. Indeed, we found significant increased expression of both RHAMM protein and mRNA in endometrial cancer compared with normal endometrium, and RHAMM protein expression correlated with tumor grade (Figure 1). Moreover, we found higher RHAMM expression in the more aggressive serous carcinomas (tumor grade 3) compared with endometrioid carcinomas (Table 1).
Figure 1. RHAMM proteins are upregulated in endometrial cancer.
RHAMM-positive tumor cells showed cytoplasmic staining and the tumors were scored as 0, 1+ (A, 1–5% of tumor cells), 2+ (B, 5–20%), or 3+ (C, >20%) based on the percentage of RHAMM-positive tumor cells, irrespective of staining intensity. All three examples shown here are serous endometrial carcinoma. (Magnification, 200X).
RHAMM protein expression has been reported as a negative prognostic factor in large cell lung carcinoma and pancreatic ductal adenocarcinoma (28,29), and we found that higher RHAMM mRNA expression predicts poor outcomes in lung adenocarcinoma (P < 0.01) (21). A previous study of 104 cases of endometrioid-type endometrial carcinomas using RHAMM IHC found that RHAMM protein expression did not show a statistically significant correlation with survival rate, but it showed a trend toward statistical significance (P = 0.057) (20). Here, we found that high RHAMM mRNA expression correlates with inferior survival in the 365 cases of endometrial cancer in the TCGA cohort, which includes 57 cases of serous carcinoma (P < 0.05, Figure 2B). This is consistent with the notion that RHAMM is more highly expressed in serous carcinomas, which is more aggressive and has higher morbidity.
We have previously demonstrated that overexpression of RHAMMv3 (RHAMMB) isoform significantly promotes metastasis of pancreatic neuroendocrine tumors in mice (30). We also demonstrated that this isoform is predominantly expressed in lung adenocarcinomas (21). In addition, it has recently been shown that RHAMM promotes growth, invasiveness, and dissemination of colorectal cancer (15). Rein et al. reported that the positivity rates for RHAMM were 100% in endometrioid carcinomas in patients with positive lymph nodes (19), and Klaric et al. reported that RHAMM protein expression correlates with myometrial invasion and LVI in endometrioid carcinomas (20). Here, we found a significant correlation between RHAMM expression and LVI when both types of endometrial cancer were combined (Table 1, P = 0.003). There is a trend toward correlation between RHAMM expression and LVI in endometrioid carcinomas, albeit not at a statistically significant level (Table 2, P = 0.053). In serous carcinomas, however, there is no correlation between RHAMM expression and the presence of LVI (Table 3). One possible explanation for this is that since most serous carcinoma cases had moderate or strong RHAMM expression, any correlation between RHAMM expression and LVI was muted or not observed. LVI is also more likely to be present in endometrial serous carcinomas compared with endometrioid carcinomas. Indeed, our dataset shows that 45.5% of serous carcinomas cases had LVI, whereas only 22.5% of endometrioid cases had LVI. In addition, we found that RHAMM protein expression in the primary endometrial cancer showed a trend toward statistical significance with the presence of metastasis (Table 1, P = 0.073). Future studies analyzing RHAMM expression in metastatic tumors compared with the corresponding primary tumors may be of interest. Overall, our data show that increased RHAMM expression correlates with biologically more aggressive endometrial cancers, specifically serous endometrial carcinoma. Within endometrial serous carcinomas, however, there is no correlation between RHAMM expression and advanced tumor stage. This finding indicates that RHAMM is not a prognostic indicator for serous endometrial carcinoma. In the TCGA mRNA data analysis, we found that both RHAMMv3 mRNA and RHAMMv4 mRNA are significantly upregulated in serous carcinomas compared with endometrioid-type carcinomas (Figure 2D). RHAMMv3 and/or RHAMMv4 may therefore contribute to the invasiveness of endometrial cancer. These two isoforms, RHAMMv3 and RHAMMv4, lack exon 4 (21). It is possible that loss of exon 4 confers oncogenic functions of RHAMM. Further mechanistic studies are required to address this hypothesis.
In addition to its cytoplasmic and spindle subcellular location, RHAMM is found on the cell surface in several cell lines (15,31). This membranous RHAMM expression along with its increased expression in endometrial cancer provides a window of opportunity for anti-RHAMM targeted therapy. In summary, our study suggests that RHAMM is a prognostic factor for endometrial cancer. Increased RHAMM expression in endometrial cancer is indicative of high-grade morphology, and RHAMMv3 and/or RHAMMv4 may contribute to endometrial cancer progression. RHAMM may be a valuable therapeutic target in endometrial cancers.
Acknowledgments
The authors thank members of the Du lab, Joanna SY Chan for contributing TMA construction, Cathleen Matrai for providing samples, and Translational Research Program at WCM Pathology and Laboratory Medicine, especially Bing He, Mai Ho, Leticia Dizon, and Pedro Brenes Retana, for technical support. This study is supported in part by DOD grant W81XWH-16-1-0619 (Y.-C.N.D.) and NIH grant 1R01CA204916 (Z.C. and Y.-C.N.D.).
Abbreviations
- HA
hyaluronic acid
- H&E
hematoxylin and eosin
- IHC
immunohistochemistry
- LVI
lymphovascular invasion
- RHAMM
the receptor for hyaluronan-mediated motility
- TCGA
The Cancer Genome Atlas
- TMA
tissue microarrays
Footnotes
The authors declare no conflicts of interest.
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