Gao Yuhan, De Swapnali, Brazil Derek P
Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
Cells. 2025 Apr 11;14(8):578. doi: 10.3390/cells14080578.
Cancer remains a leading cause of death globally, characterized by uncontrolled cell proliferation, tumor growth and metastasis. Bone morphogenetic proteins (BMPs) and their growth differentiation factor (GDF) relatives are crucial regulators of developmental processes such as limb, kidney and lung formation, cell fate determination, cell proliferation, and apoptosis. Cancer stem cells (CSCs) are a subpopulation of self-renewing cells within tumors that possess stemness properties and a tumor cell-forming capability. The presence of CSCs in a tumor is linked to growth, metastasis, treatment resistance and cancer recurrence. The tumor microenvironment in which CSCs exist also plays a critical role in the onset, progression and treatment resistance in many cancers. Growth factors such as BMPs and GDFs counterbalance transforming growth factor-beta (TGF-β) in the maintenance of CSC pluripotency and cancer cell differentiation. BMP signaling typically functions in a tumor suppressor role in various cancers by inducing CSC differentiation and suppressing stemness characteristics. This differentiation process is vital, as it curtails the self-renewal capacity that characterizes CSCs, thereby limiting their ability to sustain tumor growth. The interplay between BMPs and their secreted antagonists, such as GREM1, Noggin and Chordin, adds another layer of complexity to CSC regulation. Human cancers such as gastric, colorectal, glioblastoma, and breast cancer are characterized by GREMLIN1 (GREM1) overexpression, leading to inhibition of BMP signaling, facilitating the maintenance of pluripotency in CSCs, thus promoting tumorigenesis. GREM1 overexpression may also contribute to CSC immune evasion, further exacerbating patient prognoses. In addition to BMP inhibition, GREM1 has been implicated as a target of fibroblast growth factor (FGF) → Sonic hedgehog (Shh) signaling, as well as the Wnt/Frizzled pathway, both of which may contribute to the maintenance of CSC stemness. The complex role of BMPs and their antagonists in regulating CSC behavior underscores the importance of a balanced BMP signaling pathway. This article will summarize current knowledge of BMP and GREM1 regulation of CSC function, as well as conflicting data on the exact role of GREM1 in modulating CSC biology, tumor formation and cancer. Targeting this pathway by inhibiting GREM1 using neutralizing antibodies or small molecules may hold early-stage promise for novel therapeutic strategies aimed at reducing CSC burden in cancers and improving patient outcomes.
癌症仍然是全球主要的死亡原因，其特征是细胞不受控制地增殖、肿瘤生长和转移。骨形态发生蛋白（BMPs）及其生长分化因子（GDF）家族成员是肢体、肾脏和肺部形成等发育过程、细胞命运决定、细胞增殖和细胞凋亡的关键调节因子。癌症干细胞（CSCs）是肿瘤内具有自我更新能力的细胞亚群，具有干性特征和形成肿瘤细胞的能力。肿瘤中CSCs的存在与肿瘤生长、转移、治疗抗性和癌症复发有关。CSCs所处的肿瘤微环境在许多癌症的发生、发展和治疗抗性中也起着关键作用。诸如BMPs和GDFs等生长因子在维持CSC多能性和癌细胞分化方面可抵消转化生长因子-β（TGF-β）的作用。BMP信号通路通常在各种癌症中发挥肿瘤抑制作用，诱导CSC分化并抑制干性特征。这种分化过程至关重要，因为它减少了CSCs所特有的自我更新能力，从而限制了它们维持肿瘤生长的能力。BMPs与其分泌的拮抗剂（如GREM1、Noggin和Chordin）之间的相互作用为CSC调节增加了另一层复杂性。胃癌、结直肠癌、胶质母细胞瘤和乳腺癌等人癌症的特征是GREMLIN1（GREM1）过表达，导致BMP信号通路受到抑制，促进CSCs多能性的维持，从而促进肿瘤发生。GREM1过表达还可能导致CSC免疫逃逸，进一步恶化患者预后。除了抑制BMP外，GREM1还被认为是成纤维细胞生长因子（FGF）→音猬因子（Shh）信号通路以及Wnt/卷曲蛋白通路的靶点，这两条信号通路都可能有助于维持CSC的干性。BMPs及其拮抗剂在调节CSC行为方面的复杂作用凸显了平衡BMP信号通路的重要性。本文将总结目前关于BMP和GREM1对CSC功能调节的认识，以及关于GREM1在调节CSC生物学、肿瘤形成和癌症的确切作用的相互矛盾的数据。使用中和抗体或小分子抑制GREM1来靶向该信号通路，可能为旨在减轻癌症中CSC负担并改善患者预后的新型治疗策略带来早期希望。
