Pradhan Rajalaxmi, Paul Subarno, Acharya Sushree Subhadra, Sinha Saptarshi, Dash Somya Ranjan, Kundu Chanakya Nath
Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, Odisha, India.
Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, Odisha, India.
J Nutr Biochem. 2024 Mar;125:109568. doi: 10.1016/j.jnutbio.2024.109568. Epub 2024 Jan 6.
Tumor associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment secrete several cytokines, which involved in tumor initiation, progression, metastatic outgrowth and angiogenesis. However, the association between TAMs and CAFs in the context of tumor development remain unclear. Here, we studied the relationship between TAMs and CAFs along with the involvement of cytokines in the production of cancer-stem-like-cells (CSCs) in oral cancer cells and explored the potential anticancer effects of Nano-formulated Resveratrol (Res-NP) using an activated macrophage-M1 (AM-M1) and activated fibroblast cells as the model system. IL-6 secretion was found to be enhanced in the conditioned-medium (CM) when AM-M1 cells + CAFs-like cells were cocultured together. CSCs-enriched population was developed after addition of CM of AM-M1 +CAFs in H-357 cells and patient-derived-primary-oral-cancer cells. AM-M1 cells+ CAFs-like cells secreted IL-6 enhanced CSCs growth, proliferation, metastasis, and angiogenesis. IL-6 was found to promote PD-L1 expression in CSCs-enriched cells via JAK2/STAT3 pathway, as evident from the enhanced expression of p-JAK2 and p-STAT3. Nevertheless, Res-NP inhibited CSCs proliferation and reduced the expression of metastatic and angiogenic markers, in ovo blood vascularization, NO production and MMPs expression. Res-NP delinked the association between AM-M1 and CAFs by blocking IL-6 production and also disrupted the potential connection between IL-6 and PD-L1 with considerable decrease in p-JAK2 and p-STAT3 expressions. IL-6 depletion inhibited stemness and angiogenesis in oral CSCs by downregulating PD-L1 via JAK2/STAT3 cascade. Similar observations were also observed in Res-NP treated xenograft mice. Thus, data demonstrate that CSCs growth is dependent on IL-6/PD-L1 axis. Res-NP deregulates the association between AM-M1 and CAFs along-with attenuates carcinogenesis in in vitro, in ovo, ex vivo and in vivo model systems by inhibiting PD-L1 via IL-6/JAK2/STAT3 axis.
肿瘤微环境中的肿瘤相关巨噬细胞（TAM）和癌症相关成纤维细胞（CAF）分泌多种细胞因子，这些细胞因子参与肿瘤的起始、进展、转移生长和血管生成。然而，在肿瘤发展过程中TAM与CAF之间的关联仍不清楚。在此，我们以活化的巨噬细胞M1（AM-M1）和活化的成纤维细胞为模型系统，研究了TAM与CAF之间的关系以及细胞因子在口腔癌细胞中癌干细胞样细胞（CSC）产生中的作用，并探讨了纳米制剂白藜芦醇（Res-NP）的潜在抗癌作用。当AM-M1细胞与CAF样细胞共培养时，发现条件培养基（CM）中的白细胞介素-6（IL-6）分泌增加。在H-357细胞和患者来源的原发性口腔癌细胞中加入AM-M1+CAF的CM后，富集了CSC的细胞群得以形成。AM-M1细胞+CAF样细胞分泌的IL-6促进了CSC的生长、增殖、转移和血管生成。发现IL-6通过JAK2/STAT3途径促进富集CSC的细胞中程序性死亡配体1（PD-L1）的表达，这从磷酸化JAK2（p-JAK2）和磷酸化STAT3（p-STAT3）表达的增加中可以明显看出。然而，Res-NP抑制了CSC的增殖，并降低了转移和血管生成标志物的表达、卵内血管生成、一氧化氮（NO）的产生和基质金属蛋白酶（MMP）的表达。Res-NP通过阻断IL-6的产生解除了AM-M1与CAF之间的关联，还破坏了IL-6与PD-L1之间的潜在联系，使p-JAK2和p-STAT3的表达显著降低。IL-6的消耗通过JAK2/STAT3级联下调PD-L1，从而抑制口腔CSC的干性和血管生成。在Res-NP处理的异种移植小鼠中也观察到了类似的结果。因此，数据表明CSC的生长依赖于IL-6/PD-L1轴。Res-NP通过IL-6/JAK2/STAT3轴抑制PD-L1，从而在体外、卵内、离体和体内模型系统中解除AM-M1与CAF之间的关联，并减弱致癌作用。
