Tenascin-W Is a Novel Stromal Marker in Biliary Tract Cancers

Abstract

Extrahepatic cancers of the biliary system are typically asymptomatic until after metastasis, which contributes to their poor prognosis. Here we examined intrahepatic cholangiocarcinomas (n = 8), carcinomas of perihilar bile ducts (n = 7), carcinomas of the gallbladder (n = 11) and hepatic metastasis from carcinomas of the gallbladder (n = 4) for the expression of the extracellular matrix glycoproteins tenascin-C and tenascin-W. Anti-tenascin-C and anti-tenascin-W immunoreactivity was found in all biliary tract tumors examined. Unlike tenascin-C, tenascin-W was not detected in normal hepatobiliary tissue. Tenascin-W was also expressed by the cholangiocarcinoma-derived cell line Huh-28. However, co-culture of Huh-28 cells with immortalized bone marrow-derived stromal cells was necessary for the formation and organization of tenascin-W fibrils in vitro. Our results indicate that tenascin-W may be a novel marker of hepatobiliary tumor stroma, and its absence from many normal tissues suggests that it may be a potential target for biotherapies.

Revisiting the Tenascins: Exploitable as Cancer Targets?

“…In healthy normal breast and colorectal tissues, TN-W was not detectable at all, while their corresponding cancerous tissues displayed a robust and highly significant de novo expression of TN-W (52,88). Screening of additional human tumor types confirmed these initial observations: TN-W was strongly enriched in the stroma of brain (glioblastoma, oligodendroglioma, astrocytoma), prostate, kidney (clear cell carcinoma, papillary carcinoma, chromophobe renal carcinoma, and oncocytoma), ovarian, prostate, pancreas, biliary tract (liver carcinoma, gallbladder carcinoma), and lung cancers as well as in melanoma (48,89,90). Most significantly, TN-W was not detectable in the corresponding healthy tissues.…”

“…There is not much evidence available for the presence of specific TN-W isoforms or TN-W modifications. The only observation in this regard was gained in the Huh-28 cells, which showed a TN-W protein with a higher molecular weight than expected (89). Whether this result hints at a tumor-specific isoform, modification, or multimerization of TN-W in this cell line and whether it has any relevance in vivo remains to be seen.…”

“…Notably, when cultured alone, TN-W in Huh-28 cells was mainly observed to be intracellular without being organized and incorporated into the ECM. However, when co-cultured with bone marrow-derived stromal cells, Huh28derived TN-W organized into ECM fibrils surrounding nests of tumor cells, a situation that closely mimics the situation of tumors in vivo (89). Therefore, there is strong evidence that proper epithelial-mesenchymal crosstalk is required for formation of TN-W-positive fibrils, but also that cancer cells themselves might represent a cellular source for TN-W, which is similar to the situation for TN-C. Additional experiments, such as ISH on tumor samples, are required to fully elucidate the cell types responsible for TN-W expression and to know whether the cellular source might differ among distinct tumors.…”

“…The concept of stromal cell origin of TN-W was reinforced by observations that bone marrow-derived stromal cells exclusively expressed TN-W when co-cultured with malignant cells in a xenograft model of breast cancer cell displaying metastatic propensity toward bone (91). However, a recent study screening for TNW transcripts in 20 biliary tract cancer cell lines is challenging the idea about pure stromal cell origin of TN-W (89). While most of the cells displayed very modest or negligible TNW levels, Huh-28 cells, an intrahepatic cholangiocarcinoma cell line, showed high levels of TNW.…”

“…Accordingly, aberrant presence of TN-W in the metastatic niche, shaped and tailored by the cancer cells, provides the stimuli for increased cancer cell proliferation and migration, thereby increasing the risk for bone metastases (91). In vitro studies in biliary tract cancers revealed that TN-W fibrils are only formed in the presence of stromal cells (89). This observation might reflect such a metastatic niche as well.…”