Cancer Research Institute of Montpellier, Tumor Microenvironment and Resistance to Treatment Laboratory, INSERM U1194, Montpellier, France.
Institut National de la Santé et de la Recherche Médicale, Montpellier, France.
Theranostics. 2021 Jan 1;11(4):1626-1640. doi: 10.7150/thno.51507. eCollection 2021.
Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated and TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation . Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions , underscoring its diagnostic and therapeutic potential. TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.
结直肠癌 (CRC) 细胞传统上被认为对 TGFβ 无反应，这是由于受体和/或下游信号分子发生突变。TGFβ 仅通过间质细胞（如癌相关成纤维细胞）间接影响 CRC 细胞。然而，CRC 细胞直接响应 TGFβ 的能力目前仍未被探索。这代表了诊断和治疗干预的一个错失的机会。我们研究了原发性 CRC 和肝转移瘤中的癌细胞是否通过诱导 TGFβ 诱导的蛋白 ig-h3（TGFBI）表达来直接响应 TGFβ，以及经典和非经典 TGFβ 信号通路对这种效应的贡献。然后，我们研究了 TGFBI 对转移形成和血管生成的影响。我们使用患者的血清样本和 CRC 肝转移的原位小鼠模型，评估了针对 TGFBI 的新型抗体的诊断/肿瘤靶向价值。转移性 CRC 细胞，如循环肿瘤细胞，直接响应 TGFβ。这些细胞的特征是缺乏 TGFβ 受体突变和频繁存在 p53 突变。TGFβ 在 CRC 细胞中协调的促肿瘤发生程序是通过 TGFBI 介导的，其表达受到非经典 TGFβ 信号级联的正调控。TGFBI 抑制足以显著减少肝转移形成。此外，TGFBI 的促肿瘤发生功能与其刺激血管生成的能力有关。未经治疗的 CRC 患者的血清样本中 TGFBI 水平高于接受化疗的患者。放射性标记的抗 TGFBI 抗体选择性地靶向转移性病变，突出了其诊断和治疗潜力。TGFβ 信号在 CRC 细胞中直接有助于它们的转移潜力和对间质细胞的独立性。激活的 TGFβ 下游的蛋白，如 TGFBI，代表了用于更特异的抗转移治疗的新型诊断和治疗靶标。
