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Updated: Nov 18, 2025
Isolation of Primary Cancer-Associated Fibroblasts from a Syngeneic Murine Model of Breast Cancer for the Study of Targeted Nanoparticles
Published on: May 14, 2021
Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC
Malvika Sharma1, Ravi Chakra Turaga1, Yi Yuan1
1Department of Biology, Georgia State University, Atlanta, GA.
Abstract:
Fibrotic tumor stroma plays an important role in facilitating triple-negative breast cancer (TNBC) progression and chemotherapeutic resistance. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces apoptosis via the integrin. Cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in TNBC tumor express high levels of integrin αvβ3. ProAgio effectively induces apoptosis in CAFs and aECs. The depletion of CAFs by ProAgio reduces intratumoral collagen and decreases growth factors released from CAFs in the tumor, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, which consequently reduces tumor hypoxia and improves drug delivery. The depletion of CAFs and reduction in hypoxia by ProAgio decreases lysyl oxidase (LOX) secretion, which may play a role in the reduction of metastasis. ProAgio stand-alone or in combination with a chemotherapeutic agent provides survival benefit in TNBC murine models, highlighting the therapeutic potential of ProAgio as a treatment strategy.
Insights
ProAgio, a novel protein therapy, targets integrin αvβ3 to induce apoptosis in cancer-associated fibroblasts and endothelial cells. This approach reduces tumor fibrosis and hypoxia, enhancing chemotherapy effectiveness and improving survival in triple-negative breast cancer models.
Area of Science:
- Oncology
- Cancer Biology
- Drug Development
Background:
- Triple-negative breast cancer (TNBC) is characterized by a fibrotic tumor stroma that promotes cancer progression and chemoresistance.
- Integrin αvβ3 is highly expressed on cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) within TNBC tumors.
- Targeting integrin αvβ3 presents a potential therapeutic strategy for TNBC.
Purpose of the Study:
- To evaluate the efficacy of a rationally designed protein, ProAgio, targeting integrin αvβ3 at a novel site for TNBC treatment.
- To investigate ProAgio's mechanism of action, including its effects on CAFs, aECs, tumor microenvironment, and therapeutic resistance.
- To assess the therapeutic potential of ProAgio, alone or in combination with chemotherapy, in preclinical TNBC models.
Main Methods:
- Administration of ProAgio, a protein targeting integrin αvβ3, to TNBC murine models.
- Assessment of ProAgio's effects on CAF and aEC apoptosis, intratumoral collagen levels, growth factor release, and tumor hypoxia.
- Evaluation of ProAgio's impact on cancer cell proliferation, apoptotic resistance, and metastasis.
- Combination therapy studies involving ProAgio and a chemotherapeutic agent.
Main Results:
- ProAgio effectively induced apoptosis in CAFs and aECs expressing integrin αvβ3.
- Depletion of CAFs by ProAgio led to reduced intratumoral collagen, decreased growth factor release, and diminished cancer cell proliferation and resistance to apoptosis.
- ProAgio treatment reduced tumor hypoxia by eliminating leaky angiogenic vessels, thereby improving drug delivery.
- ProAgio decreased lysyl oxidase (LOX) secretion, potentially reducing metastasis.
- ProAgio demonstrated a survival benefit as a standalone therapy or in combination with chemotherapy in TNBC models.
Conclusions:
- ProAgio effectively targets integrin αvβ3 on CAFs and aECs, disrupting the tumor microenvironment in TNBC.
- ProAgio's ability to reduce fibrosis, normalize vasculature, and decrease hypoxia enhances chemotherapeutic efficacy and survival.
- ProAgio represents a promising therapeutic strategy for triple-negative breast cancer, warranting further clinical investigation.
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