GDF15 Propeptide Promotes Bone Metastasis of Castration-Resistant Prostate Cancer by Augmenting the Bone Microenvironment

Urology Biochemistry Oncology Medicine Life Sciences
Castration-Resistant Prostate Cancer Bone Metastasis GDF15 Biomarker Bone Microenvironment

Research Objective

This study aims to identify specific proteins secreted by prostate cancer cells through comprehensive proteomic analysis and explore their role in bone metastasis, with the goal of discovering blood biomarkers that can improve the prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC).

Research Team and Publication Information

The research was led by Gaku Yamamichi, Taigo Kato, and other researchers from the Graduate School of Medicine at Osaka University, Japan. The findings were published in 2024 in the journal Biomarker Research.

Research Process and Experimental Design

1. Secretome Analysis

Researchers conducted Orbitrap mass spectrometry analysis on the culture supernatants of four prostate cancer cell lines (LNCaP, 22Rv1, PC3, and DU145), identifying 2,787 proteins. Through secretome analysis, the researchers focused on the GDF15 propeptide (GDPP), which is secreted by prostate cancer cells, osteoblasts, and osteoclasts.

2. Functional Studies of GDPP

Researchers investigated the effects of GDPP on prostate cancer cells, osteoblasts, and osteoclasts through in vitro experiments and animal models. Experiments included cell proliferation, invasion, and migration assays, as well as the establishment of a bone metastasis mouse model.

3. Clinical Sample Analysis

Researchers collected plasma samples from 416 mCRPC patients, measured GDPP levels, and correlated them with the Bone Scan Index (BSI).

Key Findings

  1. Identification and Function of GDPP: Secretome analysis revealed that GDPP is secreted by prostate cancer cells, osteoblasts, and osteoclasts. GDPP promotes the proliferation, invasion, and migration of prostate cancer cells and exacerbates bone metastasis in mouse models. Additionally, GDPP enhances bone formation and resorption by upregulating transcription factors (e.g., RUNX2, OSX, ATF4, NFATc1, and DC-STAMP) in osteoblasts and osteoclasts.

  2. Clinical Value of GDPP as a Biomarker: In 416 mCRPC patients, GDPP demonstrated superior diagnostic ability compared to PSA and seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide, and mature GDF15). Changes in GDPP levels were significantly correlated with changes in BSI (r = 0.63), while PSA showed no significant correlation (r = -0.16).

  3. Prognostic Value of GDPP: GDPP levels were significantly associated with cancer-specific survival (CSS) and overall survival (OS) in mCRPC patients. Multivariate analysis showed that GDPP is an independent predictor of CSS and OS.

Conclusion

GDPP enhances the tumor microenvironment of bone metastasis in mCRPC and serves as a novel blood biomarker that more accurately reflects the status of bone metastasis. The detection of GDPP could reduce reliance on imaging studies and provide a basis for early therapeutic intervention in mCRPC patients.

Research Highlights

  1. Novel Biomarker: GDPP is the first blood biomarker identified for bone metastasis in mCRPC, with diagnostic capabilities surpassing existing markers.
  2. Multiple Cellular Sources: GDPP is secreted not only by prostate cancer cells but also by osteoblasts and osteoclasts, indicating its multifaceted role in the bone microenvironment.
  3. Clinical Application Potential: GDPP detection can be used for monitoring bone metastasis in mCRPC patients, reducing the need for expensive and radiation-intensive imaging studies.

Research Significance

This study not only reveals the critical role of GDPP in prostate cancer bone metastasis but also provides a new tool for the diagnosis and prognosis of mCRPC patients. As a novel blood biomarker, GDPP has the potential for widespread clinical application, helping physicians identify bone metastasis earlier and thereby improving patient outcomes and survival rates.

Future Research Directions

Although this study has made significant progress, several questions remain, such as the receptor for GDPP and its mechanism of action. Future research could focus on identifying the GDPP receptor and its specific signaling pathways in bone metastasis to develop targeted therapies. Additionally, larger-scale clinical studies are needed to validate the effectiveness of GDPP in early diagnosis and prognostic assessment.