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Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced
Sourik S Ganguly1, Paul G Daft2, Jingchen Cao3
1Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Grand Rapids, MI 49503, USA. Sourik.Ganguly@vai.org.
Abstract:
The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2 knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2 KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2 KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/β-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-β signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development.
Insights
Myeloid cell-specific TGF-β signaling drives non-small-cell lung cancer bone lesions by regulating osteoclast factors like CTHRC1 and osteoblast growth factor bFGF.
Area of Science:
- Oncology
- Bone Biology
- Cancer Metastasis
Background:
- Non-small-cell lung cancer (NSCLC) frequently metastasizes to bone, causing osteolytic lesions.
- The role of transforming growth factor-beta (TGF-β) signaling in myeloid cells during this process is unclear.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of myeloid cell-specific TGF-β signaling in NSCLC-induced osteolytic bone lesions.
- To identify key molecular mediators involved in this process.
- To elucidate the functional interplay between tumor cells, osteoblasts, and osteoclasts.
Main Methods:
- Utilized a genetically engineered mouse model with myeloid-specific knockout of Tgfbr2.
- Induced osteolytic bone lesions using H1993 NSCLC cells.
- Analyzed tumor cell proliferation, angiogenesis, and osteoclastogenesis in the bone microenvironment.
- Investigated the expression and function of C-terminal collagen related-1 (CTHRC1) and basic fibroblast growth factor (bFGF).
Main Results:
- Myeloid-specific TGF-β signaling loss in Tgfbr2 knockout mice reduced osteolytic bone lesion area.
- Bone lesion progression correlated with tumor proliferation, angiogenesis, and osteoclastogenesis.
- Basic fibroblast growth factor (bFGF) partially rescued lesion size by promoting osteoclastogenesis.
- Osteoclast-secreted CTHRC1 was downregulated in knockout mice and promoted bFGF expression in osteoblasts, potentially via the Wnt/β-catenin pathway.
Conclusions:
- Myeloid-specific TGF-β signaling promotes NSCLC-induced osteolytic bone lesion development.
- Osteoclast-derived CTHRC1 stimulates osteoblast bFGF expression, contributing to bone destruction.
- CTHRC1 and bFGF exhibit distinct cell-specific functions influencing the bone microenvironment and lesion progression.
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