Three secreted proteins — THBS1, THBS2, and PEDF — reduce the formation of blood vessels and promote the formation of cancer-associated lymphatic vessels in intrahepatic cholangiocarcinoma (iCCA), according to a new study published in the Journal of Hepatology.

Moreover, targeting THBS1, THBS2, and PEDF reduces tumor-associated lymphatic vessels formation in vivo. “Our results identify new potential targets for interventions to counteract the dissemination process in iCCA,” the authors stated.

It is known that the microenvironment in iCCA is hypovascularized, with prominent development of the lymphatic vessels, which aid in the dissemination of cancer into the liver parenchyma.

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In order to identify factors released in the iCCA stroma that drive the inhibition of angiogenesis and promote the formation of lymphatic vessels, the team led by Carmine Mancone, PhD, extracted extracellular fluid proteins from cancerous and noncancerous tissues of iCCA patients and performed quantitative proteomics on them. Then, using computational biology, they identified proteins that play a role in the regulation of vessel formation and assessed their role in 3D vascular assembly, and cell migration, proliferation, and viability. 

The researchers also investigated the formation of blood and lymphatic vessels in vivo using a mouse model. They found THBS1, THBS2, and PEDF were up-regulated in iCCA extracellular fluid and this fluid was able to inhibit vessel morphogenesis and viability in vitro. When they blocked the activity of these proteins using antibodies, tube formation was restored. Also, endothelial cell viability was similar to what is observed in the extracellular fluid of noncancerous tissue.

The experiments in the mouse model showed that the inhibition of blood vessels formation, de novo lymphangiogenesis, and the dissemination of iCCA cells in lymph nodes all depended on THBS1, THBS2, and PEDF expression.

The researchers concluded, “targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.”


Carpino G, Cardinale V, Di Giamberardino A, et al. Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma. J Hepatol. 2021;27:S0168-8278(21)01947-4. doi:10.1016/j.jhep.2021.07.016