Study Highlights BMP7 as a Potential Therapeutic Target for Ovarian Cancer

High expression of the extracellular signaling protein Bone Morphogenetic Protein 7 (BMP7) is associated with ovarian cancer progression and worsened prognosis, according to research published in the Journal of Cellular and Molecular Medicine.

Specifically, high BMP7 expression was significantly associated with aggressive phenotypes, including advanced grade, International Federation of Gynecology and Obstetrics (FIGO) stage, residual disease, and adverse overall survival.

BMP7 | Image credit: ibreakstock – stock.adobe.com

BMP7 is an extracellular signaling protein, part of the transforming growth factor-β (TGF-β) superfamily, and prior transcriptomic data has indicated potential disruption of BMP7 expression in ovarian cancer, suggesting a crucial role in the disease's aggressiveness. This study aimed to comprehensively investigate BMP7 protein expression in a substantial collection of ovarian cancer tumor samples, looking to establish associations with various clinical endpoints.

“Only a small number of studies have investigated the role of BMP7 in human carcinomas, including in prostate cancer, breast cancer, osteosarcomas, and malignant melanomas,” the researchers noted. “However, BMP7 protein expression and its potential clinical significance in ovarian carcinomas has been even less well studied.”

Utilizing ovarian carcinoma tissue samples from 575 patients who underwent surgery for various ovarian cancer subtypes, the researchers employed immunohistochemistry on both tissue microarrays and full-face tumor sections to analyze BMP7 protein expression. All patients who provided samples were treated for ovarian cancer at Nottingham University Hospitals between 1991 and 2011.

The 575 ovarian cancer specimens comprised 337 high-grade serous, 30 low-grade serous, 60 mucinous, 68 endometrioid, 53 clear cell, and 16 borderline carcinomas. The median follow-up duration was 8 years, ranging from 3 to 20 years, and patients' overall survival time spanned between 0 and 223 months (18.6 years), with a median overall survival time of 44 months.

The findings revealed a strong correlation between high BMP7 expression and aggressive clinicopathological features in ovarian cancer.

High cytoplasmic BMP7 expression was correlated with elevated tumor grade and advanced FIGO stage. This high cytoplasmic expression was also linked to high-grade serous carcinomas and the presence of residual disease, while low cytoplasmic expression was associated with mucinous, endometrioid, clear cell carcinomas, and low-grade serous carcinomas.

Similarly, high nuclear BMP7 expression showed correlations with high tumor grade and advanced FIGO stage, as well as with high-grade serous carcinoma and the presence of residual disease. Meanwhile, low nuclear expression was associated with mucinous, endometrioid, clear cell carcinomas, and low-grade serous carcinomas.

When categorizing cases by tumor stage, both cytoplasmic and nuclear expressions showed significant associations with organ-confined tumors, but no significant association was found in cancers with distant metastases. High cytoplasmic and nuclear expressions were both associated with ovarian cancers that had spread to other secondary organs.

The significant associations between elevated cytoplasmic and nuclear BMP7 expression, respectively, with each factor had the following P values:

• Advanced FIGO stage (P = .001; P < .001)
• High tumor grade (P = .005; P < .001)
• Presence of residual tumors (P = .004; P = .002)
• High-grade serous carcinomas (P < .001; P = .001)

The researchers also conducted a Kaplan-Meier survival analysis to explore the connection between BMP7 expression and both overall survival and progression-free survival. The results indicated that high cytoplasmic BMP7 and high nuclear expression were significantly associated with unfavorable overall survival, with P values of .001 and .046, respectively. However, no significant association was observed between cytoplasmic or nuclear protein expression and progression-free survival, with P values of .287 and .506, respectively.

In the multivariate analysis, incorporating factors with log-rank test P values less than .001—such as grade, histological subtypes, age, FIGO stage, platinum sensitivity, and the presence of residual tumor—neither cytoplasmic nor nuclear expression emerged as independent markers of overall survival. Conversely, FIGO stage and platinum sensitivity were identified as independent markers of overall survival.

According to the researchers, the study underscores the potential of BMP7 as both a prognostic tool and a promising target for novel ovarian cancer therapies aimed at limiting disease progression.

Reference

Vasan R, Yadav J, Aiyappa-Maudsley R, Deen S, Storr SJ, Martin SG. High BMP7 expression is associated with poor prognosis in ovarian cancer. J Cell Mol Med. 2023;27(21):3378-3387. doi:10.1111/jcmm.17951