Therapeutic Effects of Deleting Cancer-Associated Fibroblasts in Cholangiocarcinoma

Abstract

Cancer associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAF are `activated' and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma (CCA) as a desmoplastic tumor model, we investigated the sensitivity of liver CAF to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells, but lacked similar effects in quiescent fibroblasts or CCA cells. Unlike CCA cells, niether CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAF or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAF appeared to be due in part to upregulation of the pro-apoptotic protein Bax. shRNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors and apoptotic cell death. In a syngeneic rat model of CCA, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAF in the tumor microenvironment as a general strategy to attack solid tumors.

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

“…Although not related to EMT, a recent study [142] showed the possibility of targeting CAFs in a syngeneic rat model with a pro-apoptotic drug called Navitoclax, which suppressed tumor growth and improved host survival. Therefore, efforts should be directed to the development of targeted therapies against both tumor cells and their interactions with the surrounding stroma, in order to reduce metastasis and improve patient conditions.…”

Platelet-derived Growth Factor Primes Cancer-associated Fibroblasts for Apoptosis

“…However, achieving effective cancer cell-directed therapy has been challenging because of the diverse alterations in these transformed cells and the continued accumulation of abnormalities due to genomic instability (1,2). In contrast, the tumor stroma appears to be more genetically uniform and represents an additional therapeutic target (1,(3)(4)(5). Exploiting the dependence of cancer cells on the tumor microenvironment will require a further in-depth understanding of the dynamic reciprocal interaction between cancer cells and the surrounding stroma.…”

“…This dense stroma, which is found in a number of solid tumors, including cholangiocarcinoma, pancreatic cancer, and certain subtypes of breast cancer, has been proposed as a potential target for anticancer therapy (3,6,9,10).…”

“…Increased apoptotic sensitivity has been well described in several "activated" cell states, including CAF (3,11,12). For instance, activated T-cells at the end of an immune response and activated hepatic stellate cells (HSC) in fibrotic liver injury have an increased susceptibility to cell death (11,13).…”

“…For example, we recently reported that CAF from cholangiocarcinoma (CCA), a prototypic desmoplastic cancer for the study of CAF biology (6), are primed for apoptosis (3). In particular, the BH3 mimetic navitoclax is able to not only kill these myofibroblasts ex vivo but also inhibit tumor growth and metastasis in a syngeneic orthotopic transplantation animal model of CCA by depleting CAF from the tumor microenvironment (3). The mechanistic basis for the sensitivity of CAF to BH3 mimetics, however, is unknown.…”