Abstract
Ovarian cancer (OvCa) is the leading cause of death from gynecological malignancies. Five-year survival rate of OvCa ranges from 30–92%, depending on the spread of disease at diagnosis. Role of chemokines is well appreciated in cancer, including OvCa. However, their precise role is understudied. Here, we show clinical and biological significance of CXCR6-CXCL16 and ADAM10 in OvCa. Expression of CXCR6 and N-terminal CXCL16 was significantly higher in serous carcinoma tissues compared to endometrioid. OvCa cells (SKOV-3 and OVCAR-3) also showed higher expression of CXCR6 than normal ovarian epithelial cells (IOSE-7576) while CXCL16 was higher in SKOV-3 than IOSE-7576. Furthermore, N-terminal CXCL16 was higher in conditioned media of OvCa cells than IOSE-7576. Compared to OVCAR-3, SKOV-3 cells, which had higher CXCL16, expressed significantly higher transcripts of ADAM10, a protease that cleaves CXCL16. OVCAR-3 cells showed higher CXCR6 specific migration whereas SKOV-3 cells showed more invasion. Difference in invasive potential of these cells was due to modulation of different MMPs after CXCL16 stimulation. Higher CXCR6 expression in serous papillary carcinoma tissues suggests its association with aggressive OvCa. Increased migration-invasion towards CXCL16 implies its role in metastatic spread. Therefore, CXCR6-CXCL16 axis could be used to differentiate between aggressive versus non-aggressive disease and as a target for better prognosis.
Highlights
Ovarian cancer (OvCa) is the fourth most common cause of cancer-related deaths in women
OvCa Tissue microarray (TMA) consisting of 33 papillary serous adenocarcinoma and 27 endometrioid adenocarcinoma tissues was stained for CXCR6 and CXCL16, the sole natural ligand of CXCR6
Immune-intensity of N terminus CXCL16 was significantly (p < 0.0409) higher in serous papillary carcinoma (Mean intensity/ unit area = 6.488) compared to endometrioid (Mean intensity/unit area = 6.188) (Fig. 2A,C) whereas there was no significant difference in the immune-intensity of C terminus CXCL16 between serous papillary carcinoma and endometrioid (p = 0.1192) (Fig. 2B), median intensity was higher in serous papillary carcinoma
Summary
OvCa is the fourth most common cause of cancer-related deaths in women. Its diagnosis and treatment still remain a challenge in gynecological cancer research. Most studied of the chemokine signaling network is CXCR4-CXCL12 axis This axis is important for bone marrow homing of hematopoietic stem cells, their quiescence and in neuronal guidance. In OvCa, in particular, CXCR4 is overexpressed and correlates with reduced survival of patients It is involved in promoting cell proliferation, invasion and metastasis. Primary and metastatic OvCa cells show increased expression of CX3CR1 This chemokine receptor plays an important role in neurons and microglial cell communication. It significantly contributes to OvCa cell adhesion and proliferation Owing to their diverse physiological roles, targeting these chemokine axes will be associated with neuronal and immune toxicity. In this study we have established the association of CXCR6 with aggressive phenotype of OVCa and have shown significance of CXCR6 and CXCL16 in the biological processes a cancer cell utilizes to establish metastatic lesions
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