DNA Repair and Cytokines: TGF-β, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance

Tseng

et al. 2020

Cancers

Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.

Section: Introductionmentioning

confidence: 99%

Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression

Tseng

et al. 2020

Cancers

“…Similarly, TGF‐β, which is abundantly present in many tumors, has been demonstrated to increase the numbers of CSCs via cancer cell dedifferentiation . It is not without reason that both IL‐6 and TGF‐β have recently been defined as biomarkers of tumor malignity and radioresistance . Therefore, it has been suggested that CSCs could be indirectly eradicated by disrupting their relationship with the TME.…”

mentioning

confidence: 99%

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

Bialkowski

Jeught

Bevers³

et al. 2018

Intl Journal of Cancer

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapy-consisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-β-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms.

“…Previous study has investigated the effect of individual cytokines in the tumor microenvironment on tumor radiation resistance (15). In the present study, enhanced radioresistance of H460 cells was examined in the presence of a milieu of autocrine factors, and their effects were indicated to be independent of the presence of exosomes.…”

Section: Discussionmentioning

confidence: 88%

“…Vascular endothelial Autocrine secretions enhance radioresistance in an exosome-independent manner in NSCLC cells growth factor (VEGF) has been documented to promote malignant astrocytoma growth and radioresistance via VEGF receptor 2 (also known as kinase insert domain receptor) and co-activation of c-Raf/mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and phospholipase C/protein kinase C signaling pathways (14). In another study, the ability of cytokines to support DNA repair pathways and an ATM serine/threonine kinase-dependent DNA response were observed (15). Additionally, cell secreted exosomes, which represent extracellular microvesicles with diameters ranging from 30 to 100 nm that contain an abundance of proteins, messenger RNAs, microRNAs, and long non-coding RNAs, may contribute to tumor metastasis, angiogenesis and migration via autocrine/paracrine signaling (16).…”

Section: Introductionmentioning

confidence: 98%

Autocrine secretions enhance radioresistance in an exosome‑independent manner in NSCLC cells

Wang

Gao

et al. 2018

Int J Oncol

Radiotherapy resistance in patient with non-small cell lung cancer (NSCLC) reduces patient survival and remains a significant challenge for the treatment of NSCLC. Radiation resistance has been demonstrated to be affected by secreted factors, yet it remains unclear how autocrine secretions affect the radioresistance of NSCLC cells. In the present study, the NSCLC cell line, NCI-H460, was irradiated with γ-rays (4 Gy) and then cultured in medium from H460 cells or normal medium to examine the potential influence of cell secretions on the radiation resistance of H460 cells. Cell viability, accumulation of reactive oxygen species and DNA repair capacity were all markedly improved in the irradiated H460 cells that were cultured in conditioned medium (CM), compared with those cells cultured in normal medium. In addition, G2/M cell cycle arrest and upregulation of homologous recombination repair proteins were observed in the CM-treated cells, while exosomes secreted by H460 cells had no influence on the radiation resistance of H460 cells. Taken together, these results indicate that autocrine secretions enhance the radiation resistance of γ-irradiated H460 cells and that these secretions mainly affect the DNA repair process.