Junchi Huang - Osteoclasts in the fight against metastatic prostate cancer

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Link to the full thesis

Osteoclasts in the fight against metastatic prostate cancer

Metastasis to the skeleton is the major cause of death from prostate cancer. In the skeleton, the tumor grows in the bone marrow where the cancer cells interact with different types of bone cells. It is already known that the breakdown of bone by osteoclasts releases several substances that can drive the growth of cancer cells.

– In previous studies, we have studied how bone-generating osteoblasts* interact with prostate cancer cells and now we expanded those studies to osteoclasts*, says Junchi Huang, who has performed his thesis work at Sahlgrenska Center for Cancer Research. He has used both in vitro and in vivo models of prostate cancer in his studies.

 *Osteoclasts are the cells that break down bone tissue and in a healthy bone interact with osteoblasts to constantly renew and keep the bone tissue in good condition. Whether and in what way osteoclasts can directly affect the properties of prostate cancer cells has not previously been known.

Patients with metastatic prostate cancer are treated with androgen deprivation therapy (ADT) to decrease testosterone levels and thereby inhibit further growth of the tumor. However, a castration-resistant prostate cancer (CRPC) inevitably develops, often with activated androgen receptor (AR) signaling despite castrate levels of testosterone in the circulation.

Both osteoclasts and RUNX2 affect CRPC growth and steroidogenesis

– We have found that osteoclasts directly influence CRPC cell proliferation and apoptosis in vitro. Further, osteoclasts mediate gene expression in CRPC cells in a way that make them to be more resistant to external stress, possibly increasing treatment resistance. We also showed that osteoclasts and the transcription factor RUNX2 ** work together in mediating the steroidogenesis in CRPC cells. By inducing cancer cells to produce their own testosterone, RUNX2 could affect the AR signalling pathway and thereby growth of CRPC cells.

**RUNX2 is a protein that normally controls how osteoblasts are formed. It is already known that RUNX2 is also found in prostate cancer cells and makes them more malignant. We have seen in previous studies that osteoblasts increase the amount of RUNX2 in bone-forming prostate cancer cells.

These findings indicate that osteoclasts and RUNX2 are possible targets for future therapy that could decrease both skeleton related conditions caused by bone metastases and the tumor progression.

– We have found that both osteoclasts and RUNX2 affect key functions of prostate cancer cells. There are many drugs today that are used to treat metastatic prostate cancer and that prolong the life of these patients. Several of them aim to block the function of the AR further, something that thus seems to be counteracted by both osteoclasts and RUNX2.

Other drugs being clinically evaluated, such as PARP inhibitors, particularly target cancer cells with insufficient ability to repair their DNA, an ability that appears to be affected to some extent by osteoclasts. Drugs that inhibit the function of osteoclasts already exist and are used in prostate cancer care, mainly to protect the skeleton and counteract so-called skeletal-related events (SRE), but they unfortunately do not affect the life expectancy of patients.

 – My thesis shows a possible positive effect of combination therapy with drugs that inhibit osteoclasts and RUNX2 with several types of drugs that are relevant for treatment of patients with metastatic prostate cancer. This needs to be studied further in animal models in order to then be able to be evaluated in clinical studies on patients.