Open AccessSimultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC
Author(s) -
Malvika Sharma,
Ravi Chakra Turaga,
Yu Yi,
Ganesh Satyanarayana,
Falguni Mishra,
Zhen Bian,
Wei Liu,
Leilei Sun,
Jenny J. Yang,
Zhi-Ren Liu
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20200712
Subject(s) - cancer research , cancer associated fibroblasts , lysyl oxidase , integrin , triple negative breast cancer , angiogenesis , metastasis , tumor microenvironment , cancer cell , apoptosis , tumor progression , stroma , tumor hypoxia , cancer , biology , medicine , breast cancer , cell , immunology , extracellular matrix , microbiology and biotechnology , radiation therapy , tumor cells , biochemistry , immunohistochemistry , genetics
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.