Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors

Abstract

Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness.

Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity

“…Thus, serum levels of sCXCL16 might reflect tumour-associated ADAM activity. A similar association has previously been reported for ALCAM, an adhesion molecule also cleaved by ADAMs, with high serum sALCAM being predictive of poor survival (Carbotti et al , 2013). Indeed, in vitro inhibition of ADAM-10 and ADAM-17 enhanced CXCL16 expression on the membrane of (primary) OC cells and reduced sCXCL16 levels in culture supernatants.…”

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

“…4F). Shedding is likely to be universally present in solid tumors as it has been reported for colon cancer (10), ovarian cancer (11) and is easily detected in models of breast and prostate cancer (Suppl. Fig.…”

“…These studies suggest that ALCAM is shed by the tumor. Indeed, experimental models of ovarian cancers indicate elevated shedding of ALCAM specifically from the tumor (11). To determine if tumor-derived ALCAM is the source of elevated circulating ALCAM in prostate cancer we used species-specific antibodies to monitor circulating levels of both host (mouse) ALCAM and tumor (human) ALCAM longitudinally during orthotopic and subcutaneous growth of PC3 cells (Fig.…”

“…Based on our own work in colorectal cancer (10) and concomitant work in breast (19) as well as ovarian cancer (11), we hypothesized that ectodomain shedding of ALCAM is likely to correspond with prostate cancer progression. Furthermore, considering the dominant role of TGFβ in driving skeletal metastasis of prostate cancer (20,21) we postulated that this cytokine could influence ALCAM expression and/or shedding.…”

The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer

“…Serum ALCAM levels have also been found to be significantly higher in EOC patients than in controls, and full-length transmembrane ALCAM was detected in exosomes extracted from EOC ascites samples. Studies have shown that ALCAM is a marker of EOC and correlates with more aggressive tumors [37]. …”