FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy

Im, Jae Hong; Buzzelli, Jon N.; Jones, Keaton; Franchini, Fanny; Gordon-Weeks, Alex; Markelc, Boštjan; Chen, Jianzhou; Kim, Jin; Cao, Yuze; Muschel, Ruth J.

doi:10.1038/s41467-020-17914-x

Cited by 98 publications

(86 citation statements)

References 64 publications

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“…Macrophages are a source of bFGF and express FGFRs. Monocytes/macrophages play a functional, non-redundant role in bFGF-mediated angiogenesis revealed from early recruitment of mononuclear phagocytes preceding blood vessel formation in bFGF-driven angiogenesis in the matrigel plug assay, while in tumors, increased bFGF regulates macrophage polarization [ 51 , 53 ]. Apart from the pro-inflammatory signature, bFGF also contributes to the increased expression of a variety of pro-angiogenic growth factors in the endothelium, including itself, VEGF and angiopoietin-2 (Ang2) [ 51 , 54 , 55 , 56 ].…”

Section: Basic Fibroblast Growth Factor (Bfgf): a Pro-angiogenic Gmentioning

confidence: 99%

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Zahra

Sajib

Mikelis

2021

Cancers

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Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date.

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Section: Basic Fibroblast Growth Factor (Bfgf): a Pro-angiogenic Gmentioning

confidence: 99%

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Zahra

Sajib

Mikelis

2021

Cancers

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“…We and others have previously show that metabolic dysfunction, weight gain, and adipocyte hypertrophy are associated with increased production of FGF1 in subcutaneous adipose tissue (33,39), and activation of FGFR signaling is associated with tumor growth and resistance to endocrine therapy (33,40). Further, FGF2 has been shown to alter macrophage programming and is a critical regulator of immunity in the tumor microenvironment (41). Given the effects of weight maintenance on mammary adipocyte size and inflammation, we evaluated FGF1 levels in mammary adipose tissue from a cohort of rats in which both the adipocyte size distribution and extent of overfeeding during menopause-induced weight gain were previously measured (17).…”

Section: Resultsmentioning

confidence: 99%

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer

Wellberg

Corleto

Checkley³

et al. 2021

Preprint

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Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNFα, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multi-factorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

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“…FGF-2 has been shown to shift macrophages towards the M2-like phenotype (38). A shift in polarization could be exploited in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Phagocytosed polyhedrin-cytokine co-crystal nanoparticles provide sustained secretion of bioactive cytokines from macrophages

Wendler¹,

James²,

Jones³

et al. 2021

Preprint

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Many cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages and microglia are among so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as non-professional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune response, wound healing and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale co-crystalline protein depots, known as PODS®, that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by non-professional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding non-phagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.

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FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy

Cited by 98 publications

References 64 publications

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer

Phagocytosed polyhedrin-cytokine co-crystal nanoparticles provide sustained secretion of bioactive cytokines from macrophages

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