CSF1

Official Full Name

colony stimulating factor 1

Organism

Homo sapiens

GeneID

1435

Background

The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

Synonyms

MCSF; CSF-1; PG-M-CSF;

Protein Sequence

MTAPGAAGRCPPTTWLGSLLLLVCLLASRSITEEVSEYCSHMIGSGHLQSLQRLIDSQMETSCQITFEFVDQEQLKDPVCYLKKAFLLVQDIMEDTMRFRDNTPNAIAIVQLQELSLRLKSCFTKDYEEHDKACVRTFYETPLQLLEKVKNVFNETKNLLDKDWNIFSKNCNNSFAECSSQDVVTKPDCNCLYPKAIPSSDPASVSPHQPLAPSMAPVAGLTWEDSEGTEGSSLLPGEQPLHTVDPGSAKQRPPRSTCQSFEPPETPVVKDSTIGGSPQPRPSVGAFNPGMEDILDSAMGTNWVPEEASGEASEIPVPQGTELSPSRPGGGSMQTEPARPSNFLSASSPLPASAKGQQPADVTGTALPRVGPVRPTGQDWNHTPQKTDHPSALLRDPPEPGSPRISSLRPQGLSNPSTLSAQPQLSRSHSSGSVLPLGELEGRRSTRDRRSPAEPEGGPASEGAARPLPRFNSVPLTDTGHERQSEGSFSPQLQESVFHLLVPSVILVLLAVGGLLFYRWRRRSHQEPQRADSPLEQPEGSPLTQDDRQVELPV

Open

Disease

Inflammatory arthropathy, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

The CSF1 gene, found at the 1p13 site on human chromosomes, produces colony-stimulating factor 1 (CSF-1), a cytokine mainly responsible for the production, growth, differentiation, and functional control of the mononuclear phagocyte population. CSF-1 starts different signaling processes by connecting to its receptor, CSF-1R, which helps control the cell cycle and defense reactions. CSF-1 helps with the survival, development, movement, and control of certain immune cells called macrophages and monocytes from the bone marrow. CSF-1 is important for bone growth, the immune system, and how the reproductive system works in healthy circumstances. The active form of CSF-1 is made up of two identical parts connected by disulfide bonds and is usually created by breaking down a precursor that is attached to the membrane.

CSF1R Receptor and Function

CSF1R, the receptor for CSF-1, is part of the tyrosine kinase receptor group. The CSF1R gene, which comes from the c-fms proto-oncogene, helps send signals inside cells by using a process called tyrosine kinase activity. CSF-1 connects with CSF1R to promote the growth, survival, and development of macrophages. It also helps manage immune reactions, boosts bone breakdown, and plays a role in bone formation. CSF-1 helps change macrophages into M2-type cells, which can reduce the immune response and help tumors avoid being attacked by the immune system.

Figure 1 explores integrative strategies in pancreatic cancer, including targeting the tumor microenvironment and modulating macrophages using ultrasound and CSF1/CSF1R pathway inhibition. Figure 1. Integrative strategies in pancreatic cancer: ultrasound and CSF1/CSF1R pathway modulation. (Wang Q, et al., 2024)

Role of the CSF-1/CSF-1R Signaling Pathway

The purposes of CSF-1 and CSF-1R go beyond the control of immune cells. Studies show that many physiological and pathological processes, including inflammation, immunological response, cancer, and bone metabolism, depend on the CSF-1/CSF-1R signaling system. By interacting with its receptor CSF-1R, CSF-1 helps tumor-associated macrophages (TAMs) to be recruited and functionally active in the tumor microenvironment, hence fostering tumor proliferation, invasion, and metastases. Often closely linked with increased tumor invasibility and poor prognosis is the overexpression of CSF-1. High CSF-1 expression in various cancers helps to increase connections between tumor cells and TAMs, hence promoting malignant development.

CSF-1/CSF-1R and the Tumor Immune Microenvironment

The CSF-1/CSF-1R signaling system is very important for the immune setting in tumors. Tumor-associated macrophages (TAMs) help tumors avoid detection by the immune system by releasing substances that cause inflammation and block the immune response, which promotes tumor growth and spread. CSF-1 helps change macrophages, supports the growth of new blood vessels, and aids tumor cells in spreading to other parts of the body. The CSF-1/CSF-1R pathway is an important focus in cancer treatment using the immune system. Blocking the connection between CSF-1 and CSF-1R can lower the number of immune-suppressing cells in tumors. This can boost the immune system's ability to fight cancer and slow the growth of tumors.

CSF-1 and Macrophage Function

Macrophages are important for the defense system, especially in the area around tumors. CSF-1 helps increase the amount and effectiveness of TAMs in tumors by supporting the survival and growth of macrophages. Research has shown that CSF-1 helps increase the number of macrophages by attaching to CSF-1R. It also influences how macrophages change, guiding them to become M2-type macrophages through different processes. M2 macrophages help tumors grow, weaken the immune system, and create new blood vessels around tumors. They release substances called cytokines like IL-10 and TGF-β, which help tumor cells avoid being detected by the immune system and promote their cancerous development.

CSF-1R and Tumor Immune Evasion

Tumor immune evasion is the mechanism by which tumor cells control the host immunological response therefore fostering their proliferation. In the tumor microenvironment, too much CSF-1R activation drives TAM polarization into immunosuppressive M2-type macrophages. In this sense, CSF-1R not only promotes tumor development and metastases but also releases immunosuppressive cytokines therefore impeding efficient anti-tumor immune responses. For instance, CSF-1R activation might downregulate immune checkpoint ligands (like PD-L1), therefore blocking T cell activity and fostering tumor immune evasion. Especially in cancer therapy, blocking the CSF-1R signaling pathway has become a novel therapeutic approach as it restores immune system performance and improves tumor immune clearance.

Clinical Research and Therapeutic Prospects

Recently, study on treatments that focus on the CSF-1/CSF-1R system has advanced greatly. CSF-1R drugs like Pexidartinib (PLX3397) have shown promise in clinical studies by blocking TAM activity, boosting immune responses, and slowing down tumor growth. Researchers are now focusing on combination immunotherapy methods. This involves using CSF-1R inhibitors along with other immune checkpoint inhibitors or chemotherapy drugs. The goal is to improve treatment results and address the shortcomings of using just one type of treatment. However, blocking the CSF-1/CSF-1R pathway has challenges. One issue is that CSF-1 tightly controls liver macrophages, and the CSF-1/CSF-1R complex can change quickly. This can lead to unstable treatment and possible return effects. So, improving how we use CSF-1R inhibitors and minimizing side effects are important areas for future study.

References:

Wang Q, Wang J, et al. Targeting the CSF1/CSF1R signaling pathway: an innovative strategy for ultrasound combined with macrophage exhaustion in pancreatic cancer therapy. Front Immunol. 2024 Oct 2;15:1481247.
Sehgal A, Irvine KM, et al. Functions of macrophage colony-stimulating factor (CSF1) in development, homeostasis, and tissue repair. Semin Immunol. 2021 Apr;54:101509.

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