Novel therapies emerging in oncology to target the TGF-β pathway

Kim, Byung Gyu; Malek, Ehsan; Choi, Sung Hee; Ignatz-Hoover, James; Driscoll, James J.

doi:10.1186/s13045-021-01053-x

Cited by 253 publications

(190 citation statements)

References 134 publications

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“…For example, IL-6 signaling can be blocked by anti-IL-6 or IL-6R antibodies or by small-molecule inhibitors of the STAT3 pathway. Antagonists to the TGFβ pathway are also of considerable interest, in view of the pleiotropic effects of TGFβ on CSCs (Clara et al 2020 ; Kim et al 2021 ).…”

Section: Main Textmentioning

confidence: 99%

Macrophages and cancer stem cells: a malevolent alliance

Allavena

Digifico

Belgiovine

2021

Mol Med

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Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.

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Section: Main Textmentioning

confidence: 99%

Macrophages and cancer stem cells: a malevolent alliance

Allavena

Digifico

Belgiovine

2021

Mol Med

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Section: Introductionmentioning

confidence: 99%

“…The TGFβ signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer [ 14 , 15 , 16 ]. TGFβ is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor [ 14 , 15 , 16 ]. TGFβ-induces TIMP1 from hepatic stellate cells, subsequently bound to CD63, leading to FAK activation in hepatocellular carcinoma cells, suggesting that TIMP1 can function as a mediator of TGFβ-regulated crosstalk between stromal and cancer compartments [ 2 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells

Albini

Gallazzi

Palano

et al. 2021

Cancers

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Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16−, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP’s new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic–therapeutic roles.

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“…In the early stage of tumorigenesis, the TGF-β signaling pathway can inhibit cell proliferation and block the cell cycle from G1 to S by inducing the expression of related proteins such as p15, p21, and p27 (33). Nevertheless, TGF-β acts as a stimulating molecule in the tumor progression stage, promoting growth, in ltration, and metastasis by inducing immune escape and promoting angiogenesis and epithelial-mesenchymal transformation (34).…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Related Long Non-coding RNA Prognostic Risk Model for Gastric Cancer

Huang

Zhuang

et al. 2021

Preprint

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Background：Gastric cancer (GC) is one of the most common malignant tumors with a poor prognosis. Ferroptosis is a novel and distinct type of non-apoptotic cell death that is closely associated with metabolism, redox biology, and tumor prognosis. Recently, ferroptosis-related long non-coding RNAs (lncRNAs) have received increasing attention in predicting cancer prognosis. Thus, we aimed to construct an ferroptosis-related lncRNAs signature for predicting the prognosis of patients with gastric cancer.Methods：We built an ferroptosis-related lncRNA risk signature by using Cox regression based on TCGA database. Kaplan-Meier survival analysis was conducted to compare the overall survival (OS) in different risk groups. Cox regression was performed to explore whether the signature could be used as an independent factor. A nomogram was built involving the risk score and clinicopathological features. Furthermore, we explored the biological functions and immune states in two groups.Results：Eight ferroptosis-related lncRNAs were obtained for constructing the prognosis model in gastric cancer. Kaplan–Meier curve analysis revealed that patients in the high-risk group had worse survival than those in the low-risk group. The survival outcome was also appropriate for subgroup analysis, including age, sex, grade, and clinical stage. Multivariate Cox regression analysis and receiver operating characteristic (ROC) curve analysis demonstrated that the risk score was an independent prognostic factor and superior to traditional clinicopathological features in predicting GC prognosis. Next, we established a nomogram according to clinical parameters (age, sex, grade, and clinical stage) and risk score. All the verified results, including ROC curve analysis, calibration curve, and decision curve analysis, demonstrated that the nomogram could accurately predict the survival of patients with gastric cancer. Gene set enrichment analysis revealed that these lncRNAs were mainly involved in cell adhesion, cancer pathways, and immune function regulation.Conclusion: We established a novel ferroptosis-related prognostic risk signature including eight lncRNAs and constructed a nomogram to predict the prognosis of gastric cancer patients, which may improve prognostic predictive accuracy and guide individualized treatment for patients with GC.

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Novel therapies emerging in oncology to target the TGF-β pathway

Cited by 253 publications

References 134 publications

Macrophages and cancer stem cells: a malevolent alliance

Macrophages and cancer stem cells: a malevolent alliance

TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells

A Novel Ferroptosis-Related Long Non-coding RNA Prognostic Risk Model for Gastric Cancer

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