Cancer-associated fibroblasts orchestrate the optimal cancer stemness-enhancing microenvironment in intrahepatic cholangiocarcinoma by “educating” myeloid-derived suppressor cells, according to a new study published in Hepatology. This previously unrecognized role of cancer-associated fibroblasts could explain the highly aggressive nature of this type of cancer.  

This finding suggests that targeting cancer stemness could be a promising therapeutic approach for intrahepatic cholangiocarcinoma. 

The authors of the study had previously shown that cancer-associated fibroblasts promoted tumor growth by recruiting myeloid-derived suppressor cells. In the present study, they investigated how these cancer-associated fibroblasts regulate the function of myeloid-derived suppressor cells to increase cancer stemness.

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The researchers conducted RNA-sequencing analyses and found that metabolic pathways were enriched while inflammatory pathways were decreased in myeloid-derived suppressor cells from the tumor, compared to those from the blood in patients with intrahepatic cholangiocarcinoma.

When they injected cancer-associated fibroblasts derived from patients into a mouse model of intrahepatic cholangiocarcinoma, the researchers saw that cancer stemness was promoted in the animals. However, this was blunted by the depletion of myeloid-derived suppressor cells.

Read more about cholangiocarcinoma etiology

The role of cancer-associated fibroblasts in enhancing cancer stemness via myeloid-derived suppressor cells was further demonstrated by the fact that conditioned media from cancer-associated fibroblast-educated myeloid-derived suppressor cells drastically promoted the efficacy of tumorsphere formation and increased the expression of genes that are markers of stemness.

One of these genes was ALOX5, which encodes for 5-lipoxygenase (5-LO). Not only did cancer-associated fibroblast-conditioned media increase the expression of the gene, it also increased the activity of the enzyme, which plays a critical role in tumor progression. 

In a reverse experiment, the researchers showed that inhibiting the activity of 5-LO impaired the stemness-enhancing capacity of myeloid-derived suppressor cells.

The researchers also showed that interleukin (IL)-6 and IL-33 expressed mainly by cancer-associated fibroblasts mediated hyperactivated 5-LO metabolism in myeloid-derived suppressor cells.

Finally, the researchers showed that treatment with leukotriene B4 (LTB4), which is synthesized by 5-LO, significantly reduced the stemness-enhancing effects of cancer-associated fibroblast-educated myeloid-derived suppressor cells. The same effect was obtained with the blockade of LTB4 receptor type 2 (BLT2), the receptor to which LTB4 binds.

“We identify the LTB4-BLT2 axis as the critical downstream metabolite signaling of 5-LO in promoting cancer stemness,” the researchers wrote. Interestingly, blocking BLT2 increased chemotherapeutic efficacy, suggesting that this could be a potential therapeutic approach.


Lin Y, Cai Q, Chen Y, et al. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma via 5-lipoxygenase. Hepatology. Published online August 13, 2021. doi:10.1002/hep.32099