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Updated: Feb 22, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in
I Huber-Ruano1, C Raventós1, I Cuartas1
1Translational Research Program, Vall d Hebron Institute of Oncology (VHIO), Barcelona.
Background:
The transforming growth factor (TGF)-β pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-β pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-β isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-β2.
Materials And Methods:
We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis.
Results:
We observed that ISTH0047 is able to significantly reduce TGF-β2 mRNA and protein levels without altering the levels of TGF-β1 and TGF-β3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-β2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86.
Conclusion:
Overall, our data point to TGF-β2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.
Insights
ISTH0047, a novel drug targeting transforming growth factor-beta 2 (TGF-β2), effectively prevents lung metastasis by modulating the tumor microenvironment. This study highlights TGF-β2 as a key therapeutic target for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The transforming growth factor-beta (TGF-β) pathway is implicated in tumor immunosuppression and oncogenesis.
- Targeting the TGF-β pathway presents a promising strategy for cancer therapy.
- Specific responses to individual TGF-β isoforms remain underexplored.
Purpose of the Study:
- To investigate the antitumor efficacy of ISTH0047, an antisense oligonucleotide targeting TGF-β2.
- To evaluate the impact of ISTH0047 on TGF-β isoforms and metastasis in preclinical models.
Main Methods:
- Anticancer response to ISTH0047 assessed via gymnotic delivery in tumor cell cultures.
- Preclinical orthotopic mouse models used for primary breast and kidney tumors, and lung metastasis.
- Analysis of TGF-β mRNA and protein levels, and macrophage phenotype.
Main Results:
- ISTH0047 significantly reduced TGF-β2 mRNA and protein levels without affecting TGF-β1 or TGF-β3.
- ISTH0047 inhibited lung metastasis in renal cell carcinoma and breast cancer models.
- Treatment with ISTH0047 modulated the lung microenvironment, promoting CD86 expression in tumor-associated macrophages.
Conclusions:
- TGF-β2 is identified as a viable therapeutic target for cancer treatment.
- ISTH0047 demonstrates potential as an anticancer drug for preventing lung metastasis.
- The drug's mechanism involves impacting the tumor niche, partly via CD86 induction in macrophages.
