The origin of cancer-associated cells revealed?

Japanese researchers have revealed what they claim to be the origins of cancer-associated fibroblasts — cells that play a key role in cancer progression — in a breakthrough that could lead to new approaches to cancer treatment.

The tumour microenvironment contains various types of cells, including so-called cancer-associated fibroblasts (CAFs). CAFs play an important role in various aspects of cancer progression, such as tumour growth, inflammation, drug resistance and metastasis. However, it is still unclear how CAFs themselves are generated.

Now, researchers led by Masaharu Seno from Okayama University have hypothesised that CAFs originate from cancer stem cells (CSCs), which can develop into any type of cell occurring in a given tumour. They tested their theory by creating CSC-like cells following a protocol they had established earlier: exposing mouse induced pluripotent stem cells (miPSCs) — a type of reprogrammed cell with an embryonic-like pluripotent state which can differentiate into any type of cell — to a conditioned medium prepared from the culture of human breast cancer cell line.

The resulting cells displayed a typical CSC-like phenotype, exhibiting three essential features of CSCs. The first feature is self-renewal, which is attributed to a potential to form spheres in serum-free suspension cultures. The second is the ability to form malignant tumours in vivo. The third and most crucial feature is the potential for differentiation, with the CAF phenotype found to be one of the many phenotypes that CSCs can differentiate into.

The researchers then separated fibroblast-like cells differentiating from CSC-like spheres in the presence of conditioned medium. These cells were compared with fibroblast-like cells generated directly from miPSCs. Comparative analysis revealed that CSC-generated fibroblast-like cells displayed the CAF-like phenotype. The researchers concluded that the conditioned medium plays a key role in the differentiation of CSC-like spheres into CAFs.

Finally, the expression of CAF markers (proteins that are associated with the formation of CAFs) was analysed. The scientists found that CAFs have high invasive potential when compared with normal fibroblasts. This indicates that CSCs are a source of CAF-like cells in the tumour microenvironment.

Writing in the journal Scientific Reports, the researchers stated that “inhibiting the conversion of CSCs to CAFs might have potential therapeutic implications in the future”. They noted that if therapeutic strategies can be designed to inhibit CSC-to-CAF conversion, cancer progression may be halted.