Background & Aims A therapeutically challenging subset of cells, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche. Methods CCA cells were cultured in 3D conditions to generate spheres. CCA sphere analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed. The in vitro and in vivo effect of CCA spheres on macrophage precursors was tested after culturing healthy donor cluster of differentiation (CD)14+ with CCA-sphere conditioned medium. Results CCA spheres engrafted in 100% of transplanted mice and revealed a significant 20.3-fold increase in tumor-initiating fraction (p = 0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA spheres were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. Next, fluorescence-activated cell sorting analysis showed that in the presence of CCA sphere conditioned medium, CD14+ macrophages expressed key markers (CD68, CD115, human leukocyte antigen-D related, CD206) indicating that CCA sphere conditioned medium was a strong macrophage-activator. Gene expression profile of CCA sphere activated macrophages revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated macrophages from CCA resections recapitulated a similar molecular phenotype of in vitro-educated macrophages. Consistent with invasive features, the largest CD163+ set was found in the tumor front of human CCA specimens (n = 23) and correlated with a high level of serum cancer antigen 19.9 (n = 17). Among mediators released by CCA spheres, only interleukin (IL)13, IL34 and osteoactivin were detected and further confirmed in CCA patient sera (n = 12). Surprisingly, a significant association of IL13, IL34 and osteoactivin with sphere stem-like genes was provided by a CCA database (n = 104). In vitro combination of IL13, IL34, osteoactivin was responsible for macrophage-differentiation and invasion, as well as for in vivo tumor-promoting effect. Conclusion CCA-CSCs molded a specific subset of stem-like associated macrophages thus providing a rationale for a synergistic therapeutic strategy for CCA-disease. Lay summary Immune plasticity represents an important hallmark of tumor outcome. Since cancer stem cells are able to manipulate stromal cells to their needs, a better definition of the key dysregulated immune subtypes responsible for cooperating in supporting tumor initiation may facilitate the development of new therapeutic approaches. Considering that human cholangiocarcinoma represents a clinical emergency, it is essential to move to predictive models in order to understand the adaptive process of macrophage component (imprinting, polarization and maintenance) engaged by tumor stem-like compartment.
Raggi, C., Correnti, M., Sica, A., Andersen, J., Cardinale, V., Alvaro, D., et al. (2017). Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. JOURNAL OF HEPATOLOGY, 66(1), 102-115 [10.1016/j.jhep.2016.08.012].
|Citazione:||Raggi, C., Correnti, M., Sica, A., Andersen, J., Cardinale, V., Alvaro, D., et al. (2017). Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. JOURNAL OF HEPATOLOGY, 66(1), 102-115 [10.1016/j.jhep.2016.08.012].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages|
|Autori:||Raggi, C; Correnti, M; Sica, A; Andersen, J; Cardinale, V; Alvaro, D; Chiorino, G; Forti, E; Glaser, S; Alpini, G; Destro, A; Sozio, F; Di Tommaso, L; Roncalli, M; Banales, J; Coulouarn, C; Bujanda, L; Torzilli, G; Invernizzi, P|
INVERNIZZI, PIETRO (Ultimo)
|Data di pubblicazione:||2017|
|Rivista:||JOURNAL OF HEPATOLOGY|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jhep.2016.08.012|
|Appare nelle tipologie:||01 - Articolo su rivista|