Abstract
Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor metastases. From these data we conclude that PDAC patients with high activin A expression in stroma have a worse prognosis. PSCs secrete activin A, promoting increased PDAC migration. Inhibition of activin A in mice decreased metastases. Hence, stroma-rich PDAC patients might benefit from activin A inhibition.
Highlights
Normal PDAC/pancreatic cancer (PC) epithelial cells[14]
We utilized a neutralizing antibody against activin A for systemic inhibition of ligand-receptor interaction in tissue culture models and in mice with tumor burden to determine the impact on cancer cell migration and metastasis
To investigate if activin A protein levels are elevated in human PDAC tumor tissue, we performed histological immunostaining (IHC) on a tissue microarray (TMA) of human pancreatic cancer tissue and matching adjacentnormal tissue (n = 63, matching pairs) (Fig. 1A) where data on gender, age, stage, grade and survival were provided (Figure S1B)
Summary
We have shown that increased tumor microenvironment stiffness promotes activin A secretion from colon stromal cells, which enhances migration of colon cancer epithelial c ells[13]. Evidence indicates that activin A signaling is important in a number of cancers including c olorectal14,21,22, mammary23, lung24, esophageal[25] and p ancreatic[26]. Together these studies indicate that activin A is important in pancreatic cancer, but do not address the mechanisms by which activin A is increased or how it promotes pancreatic cancer metastasis. We utilized a neutralizing antibody against activin A for systemic inhibition of ligand-receptor interaction in tissue culture models and in mice with tumor burden to determine the impact on cancer cell migration and metastasis
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