The Roles of Glycodelin in Cancer Development and Progression.

Glycodelin expression in cancers is regulated by diverse cells and molecules. Stromal paracrine signals may play a role in the regulation of glycodelin expression. The stromal cells in endometrium induce the production of glycodelin both in endometrial cancer cells (Ishikawa cells) ( 14 ) and in normal endometrial epithelial cells ( 93 ). It can be postulated that glycodelin may interact with cancer microenvironment to modulate cancer development. Lysophosphatidic acid (LPA) is overexpressed in many malignancies especially gynecologic cancers ( 94 , 95 ). LPA can increase glycodelin expression in cervical cancer (Hela cells), endometrial cancer (RL-95 cells), and ovarian cancer (OVCAR-3 cells) but not in breast cancer (MDA-MB-231 cells) ( 96 ), which further implies that glycodelin may be involved in LPA-induced signaling to participate in cancer development and progression. As a kind of promising anticancer drug, histone deacetylase inhibitors (HDACIs) regulate cancer development and the expression of cancer-related genes ( 97 ). Glycodelin is upregulated by HDACIs, trichostatin A, and suberoyl anilide hydroxamic acid, which further speeds the migration of Ishikawa endometrial adenocarcinoma cells ( 98 ) but promotes cell differentiation to the normal epithelium characteristics ( 99 ), which generates a dilemma in the clinical use of HDACIs for anticancer treatment. Relaxin, a mediator to promote the progression of various cancers such as endometrial cancer and breast cancer, activates glycodelin expression in endometrial glandular epithelial cells in vitro . The serum expression profiles of glycodelin and relaxin are closely correlative and glycodelin expression in human serum also increases following relaxin administration in vivo ( 100 , 101 ). Taylor et al. further elucidated that relaxin inhibited progestin-stimulated activation of glycodelin in Ishikawa cells rather than regulating glycodelin production directly ( 102 ).

JC, YL, and XW conceived the idea, and JC and YL wrote the article. All authors reviewed the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Glycodelin is extensively known as a kind of glycoprotein whose glycans and protein structures mediate various actions in human reproductive activities. There are four known isoforms of glycodelin to date, GdA, GdS, GdF, and GdC. Due to the specific glycosylation, GdA rather than other isoforms occupies the majority of glycodelin, and in early researches it is proved to play an indispensable role in fetomaternal immunity. Thus recent researches pay more attention to the role of GdA in cancer development and progression. Whether other isoforms of glycodelin also participate in cancer development and progression need further investigations. Glycodelin expression is closely related to the diagnosis and prognosis of cancer patients; and therefore, it could be a potential biomarker for early diagnosis and recurrence monitoring of cancer patients. Dependent on the abilities to regulate cell proliferation, differentiation, and invasion and promote angiogenesis, glycodelin can remodel the cancer microenvironment and adjust the expression of cancer-related genes and the presentation of cell surface molecules. The specific expression of glycodelin in cancers may provide a general mechanism to facilitate cancer development and progression. The present researches have illustrated the immunologic effects of glycodelin to multiple immune cells, and the investigated immune cells are mostly isolated from PBMC, which can be extended to the correlation between glycodelin and cancer immunity. Additionally, glycodelin expressed in the normal hematopoietic cells, including megakaryocytic lineage and erythroid precursors ( 103 , 104 ), indicates that glycodelin is also involved in the human entire immune activities not just in the local reproductive immunity. However, there are some limitations that cannot be ignored. First, some controversial results are presented about prognostic value of glycodelin in cancer patients. These discrepancies may rely on different detection methods or reagents. It would be of great significance to produce quality antibodies and establish considerable standards for glycodelin detection. Second, parts of the reported studies are of relatively small sample size. Studies with large sample size or systemic meta-analysis on the correlation of glycodelin expression with cancer patient prognosis need be further explored. Third, the role of glycodelin A in cancer development and progression is well investigated and mainly discussed in the review, but the roles of other glycodelin isoforms, including GdS, GdF, and GdC, have not been fully revealed due to various limitations. Finally, as a kind of reproduction-related glycoprotein, normal secretory endometrium of females is a main source of glycodelin in physiological conditions, so glycodelin is indicated of more significance in female-specific cancers such as endometrial cancer, ovarian cancer, and breast cancer. Besides, in non-gender specific cancers such as lung cancer, female NSCLC patients with lymph node metastases have higher glycodelin secretion and higher glycodelin expression in female NSCLC patients indicates a poorer overall survival rate ( 41 ). Thus glycodelin may be of greater importance for female patients. In the past decades, immunotherapy has become the main breakthrough in cancer therapy by overcoming cancer immune evasion ( 105 ). The current clinical success, immune checkpoint inhibitors, is aimed to unleash antitumor immunity to eliminate cancer cells by specific blocking antibodies to cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), two inhibitory receptors in T cells to limit lymphocyte activation ( 106 ). It is well desired to investigate that whether glycodelin participates in the regulation of negative costimulatory signaling pathways, like CTLA-4/B-7 and PD-L1/PD-1 and other T cell subsets such as Th17 and regulatory T cells. When PD-L1/PD-1 pathway is blocked in cancer, the polarization of effector T cells is skewed in the balance of Th1/Th17 ( 107 ). Treg cells can accelerate the immune privilege in cancer ( 108 ) and if glycodelin produces immunoregulatory effects to Treg cells, it will provide further evidence for how glycodelin participates in cancer immunity.

Glycodelin, also known as pregnancy-associated α2-globulin, placental protein 14, or progesterone associated endometrial protein, is a kind of glycoprotein mainly derived from secretory endometrium, pregnancy deciduas, and amniotic fluid ( 1 , 2 ). With its distinct glycans and characteristic carbohydrate structure, glycodelin mediates various biological activities in human reproduction and fetomaternal immunity ( 2 , 3 ). To date, there are four different isoforms of glycodelin identified according to their differences in glycosylation, which are glycodelin A (GdA) mainly from amniotic fluid and pregnancy decidua ( 4 , 5 ), glycodelin S (GdS) from seminal plasma ( 6 ), glycodelin F (GdF) from ovarian follicles ( 7 ) and glycodelin C (GdC) from cumulus oophorus ( 8 ). The four isoforms of glycodelin exert their distinctive biological functions mainly relying on the protein backbone as well as the glycosylation ( 3 ) (Table 1 ). Different isoforms of glycodelin. Gd, glycodelin .