MicroRNAs Regulate Small-Cell Lung Cancer Bone Metastasis

Researchers have identified a novel pathway that promotes bone metastasis of small-cell lung cancer (SCLC). The study is in mice, but points to a potential target that could be exploited to control or prevent metastatic disease. The results are published in Molecular Cancer Research.

Xijie Yu, MD, PhD, of the West China Hospital and Sichuan University in China, and colleagues identified a microRNA, miR-335, that, at least in preclinical small-cell lung cancer (SCLC) models, is responsible for levels of two key mediators of bone metastases, RANKL and the insulin growth factor receptor 1 (IGF-R1).

Prostate, breast, and lung cancer tumors tend to metastasize to bone tissue. But while the mechanisms of seeding distant tumors in bone tissue has been relatively well studied in prostate and breast, the pathways important for lung cancer bone metastasis are relatively unknown.

IGF-1R has been previously linked to the ability of cancer cells to seed metastatic tumors in the bone. RANKL is a regulator of bone tissue generation and the target of antibody therapies that can inhibit bone metastasis. RANKL inhibitors such as denosumab are used in the clinic to try to minimize pain from metastatic bone tumors.

Roles of different microRNAs in controlling the expression of genes important in tumorigenesis-both promoting and inhibiting tumor growth-has recently been uncovered.

In the current study, Yu and colleagues took advantage of an observation that while one cell line derived from a SCLC tumor had a proclivity for bone metastasis, another SCLC cell line formed metastases only in non-bone tissue in mouse models. Comparing the microRNA expression profiles of the two cell lines showed that miR-335 were low in cells that homed to bone tissue. Increasing expression of the microRNA inhibited bone metastases in mice.

Further experiments showed that both IGF-1R and RANKL are targets of miR-335.

SCLC accounts for approximately 10% to 15% of all lung cancer cases and is associated with patients who have a history of smoking. SCLC tends to progress rapidly and relatively few advances in treatment of advanced forms of the disease have been made in decades. More than one-third of SCLC patients develop bone metastases. Still, the most common treatment remains chemotherapy which does little to treat painful bone disease or prevent bone fractures associated with metastases.

These findings can potentially be applied to bone metastasis in breast and prostate cancer, said Brian Ell, a PhD candidate at Princeton University who studies mechanisms of bone metastasis in the laboratory of professor Yibin Kang.

This study suggests that targeting miR-335 could be used in a similar manner to the inhibition of RANKL with antibodies, said Ell. Still, more studies are needed to understand the role of miR-335 and other microRNAs and proteins in promoting bone metastasis of SCLC tumors. Whether the same mechanism also facilitates bone metastasis of prostate and breast tumors remains to be seen. Before miR-335 based therapies can be developed, “it is important that the miRNA is properly tested for effects in other cells, and to make sure it does not have any additional targets that could produce unforeseen effects on the patients,” said Ell.

Thus far, microRNA based therapies are in development but their utility in treating cancer patients remains to be demonstrated.