Colony Stimulating Factors - their unique biological roles and therapeutic benefits

Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to receptor proteins on the surfaces of hematopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell, usually white blood cells. They play part in the hosts´ response to injury and infection, and although they were originally defined as haematopoietic cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional unique biological functions, suggesting that they could be used to target specific conditions.

Mechanism of action

Many tissues can produce CSF:s when appropriately stimulated with inflammatory mediators such as LPS, TNF-alpha, IFN-beta, VEGF, IL-17 and IL-1, thus inducing expression in endothelial cells, macrophages, epithelial cells and fibroblasts. 

These colony-stimulating factors are soluble substances, and transduce by paracrine, endocrine, or autocrine signaling. CSF:s bind to receptor proteins (CSFRs) on the surfaces of hematopoietic stem cells,  activating intracellular signaling pathways that can cause the cells to proliferate and differentiate.

The CSF family includes:

  • Granulocyte–colony-stimulating factor (G-CSF)
    G-CSF stimulates the production of polymorphonuclear (PMN ) leukocytes, which are necessary for the ingestion and intracellular destruction of bacteria. It is often used to increase neutrophil numbers and decrease infections in patients with non-myeloid malignancies. It is also indicated in patients with acute myeloid leukemia, bone marrow transplants, and severe, chronic neutropenia.

  • Granulocyte-macrophage–colony-stimulating factor (GM-CSF)
    GM-CSF is secreted by a wide variety of lymphoid and non-lymphoid cells. Stimulation of stem cells induces maturation and differentiation of granulocytes (e.g., PMNs, eosinophils, and basophils) and monocytes.

  • Multiple-colony-stimulating factor, or interleukin 3 (IL-3)
    Multiple-CSF/IL-3 stimulates bone marrow stem cells to differentiate into myeloid progenitor cells. It also stimulates the proliferation of mature granulocytes, monocytes, and dendritic cells. IL-3 is secreted by lymphocytes, epithelial cells, and astrocytes. The role of IL-3 in disease is unclear.

  • Macrophage–colony-stimulating factor (M-CSF)
    M-CSF is a non-glycosylated protein that induces the mobilization and differentiation of macrophage precursors. When used in conjunction with G-CSF, it also mobilizes endothelial cell precursors and revascularizes ischemic tissue.

CSF as a pharmaceutical target

Traditionally, colony stimulating factors are used in patients who are undergoing cancer treatment that causes low white blood cell counts (neutropenia) and puts the patient at risk of infection. Treatment with CSFs reduces the time where patients are neutropenic.

Administration of non endogenous/foreign CSFs stimulates the stem cells in the bone marrow to produce more white blood cells. These new white blood cells then migrate into the blood and serve as a boost to the patiens own impaired immune system.

There is a great interest in targeting these different Colony Stimulating factors in inflammatory and autoimmune disorders, as well as in cancer. Most CSF:s compounds of today are expensive and require cumbersome systemic administration. New CSF analogues are represented primarily by biosimilars where the originator drug has gone of patent.

All different CSFs  have unique biological roles, suggesting that they may have therapeutic benefits for the treatment of diseases ranging from various cancer forms, viral infections, and autoimmune diseases and as a result, many clinical trials targeting colony-stimulating factors are now well on there way.

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