Therapeutic potential of fractalkine: a novel approach to metastatic colon cancer

Short abstract

Fractalkine is involved in the pathogenesis of different types of cancer and in various clinical disease states

Several experimental approaches have shown that a variety of chemokines have anti‐tumour activity either by chemoattracting natural killer cells, monocytes and macrophages, or by accumulating dendritic cells.¹ Accumulating evidence has shown that fractalkine (CX3CL1), the unique member of the CX3C chemokine subfamily, is involved in the pathogenesis of different types of cancer²,³ and in various clinical disease states beyond cancer, such as atherosclerosis, glomerulonephritis, rheumatoid arthritis, HIV disease and sepsis.⁴,⁵,⁶ In contrast with other chemokines, fractalkine exists in two forms, each mediating distinct biological actions.⁷ The membrane‐anchored protein, which is expressed primarily on the endothelium, serves as an adhesion protein promoting the retention of monocytes and T cells.⁸ The soluble form originates from extracellular proteolysis by proteases, such as tumour necrosis factor‐α converting enzyme (also known as ADAM17) and ADAM10.⁹ The secreted form resembles more a conventional chemokine and strongly induces chemotaxis and causes migration of natural killer cells, cytotoxic T lymphocytes and macrophages. Both chemotaxis and adhesion are mediated by the G protein‐coupled receptor CX3CR1,¹⁰ which is present on natural killer cells, CD14+ monocytes and on some subpopulations of T cells.

In a variety of pathological conditions, fractalkine may cause excessive attraction and activity of cytotoxic lymphocytes, which might lead to vascular and tissue damage. This has been shown for patients with coronary artery disease, where fractalkine plasma levels were greatly increased, especially in unstable disease,⁶ leading to plaque instability and rupture. Fractalkine plays an important part not only in the binding of natural killer cells to endothelial cells but also in natural killer cell‐mediated endothelial damage, which might result in atherosclerosis and vascular injury.¹¹ Moreover, fractalkine expression is markedly enhanced in acute allograft rejection, in which fractalkine contributes to an intense cellular immune response and to an influx of circulating leucocytes into the transplant. Treatment of recipients with anti‐CXCR1‐blocking antibodies has been shown to markedly prolong allograft survival.¹² Similarly, in glomerulonephritis, immunoneutralisation of the fractalkine receptor dramatically blocked leucocyte infiltration into the glomeruli and improved renal function, suggesting a role for fractalkine in the pathogenesis of human glomerulonephritis.¹³ Taken together, these reports indicate that fractalkine may be expressed in many tissues and may be detrimental to several inflammatory diseases by promoting the accumulation of CX3CR1‐positive immune cells at inflammation sites.

However, in disease states with impaired local and systemic immune responses, fractalkine can induce potent anti‐tumour and tissue‐protective effects, as shown for HIV infections and various cancer types. In patients with HIV, increased expression of fractalkine protects neurones from neurotoxins, which have key roles in neural apoptosis in the brain.¹⁴ Certain polymorphisms of the fractalkine receptor CX3CR1 influence the progression of HIV infection to the full stage of AIDS and underline the importance of fractalkine in this disease.¹⁵

In addition to HIV disease, cancer is the most promising field of application of fractalkine according to recent publications: vaccination of mice with lung carcinoma cells gene modified with fractalkine induces a potent anti‐tumour response, which involves chemoattraction of natural killer cells into tumour sites.² Dendritic cells modified to express fractalkine are able to suppress tumour growth of B16‐F10 melanoma and colon‐26 adenocarcinoma cancer cells in mice.³ It is generally known that the number of tumour‐infiltrating lymphocytes in patients with colorectal cancer can be considerably few. Ohta et al¹⁶ showed that a higher level of expression of fractalkine in patients with colorectal cancer correlates with a higher density of tumour‐infiltrating immune cells and results in a better prognosis than in those with a weak expression. Therefore, the expression of fractalkine may be considered to be an essential biomarker for predicting prognosis and for identifying those patients who might benefit most from additional immunomodulating therapy.

In this issue of Gut, Vitale et al¹⁷(see page 365) confirm previous studies and extend our knowledge of fractalkine in metastatic colon cancer. They developed C26 colon cancer cells expressing the native (wild‐type), the soluble or the membrane‐bound form of fractalkine. In murine models of skin tumours, liver and pulmonary metastasis, native fractalkine expression by C26 colon cancer cells drastically reduced their overall metastatic potential and growth in the target organs. Whereas the secreted form reproduced many of the effects of wild‐type fractalkine, the membrane‐bound variant exerted opposing effects, varying from tumour suppression to enhancement, depending on the target tissue and the experimental model. The overall effect of fractalkine resulted from a critical balance between the activity of the secreted and membrane‐anchored forms. Moreover, these data underscore the importance of using relevant animal models to investigate novel anti‐cancer strategies. The authors show that distinct immune mechanisms, especially accumulation of CD8+ cells in the skin and activation of CD4+ cells in the liver, contribute to the tumour‐suppressive activity of fractalkine, depending on the target organs and the tumour microenvironment.

The crude mortality estimated for colon cancer is still unacceptably high, and therefore the implementation of adjunctive immunological therapies is a challenge for every oncologist. Although these initial observations¹⁷ are promising, limitations for the use of fractalkine vaccination or genetic modification of immune cells with fractalkine‐expressing vectors for the treatment of colon cancer remain: any rodent model of cancer, whether it is the simple subcutaneous or the more relevant orthotopic model of liver or lung cancer resembles the physiological response of a primate only to a certain degree. Extrapolation of data from small laboratory animals cannot reliably predict human responses because of interspecies differences. Potential side effects, such as damage to normal tissues or vascular injury in organs apart from the tumour, have not been described in animal models yet, but can be expected in humans. In addition, little is known about the most suitable point of time or the most susceptible tumour stage for an immune therapy with fractalkine. New approaches to the modulation of the immunological response have been studied in animals, which require further verification in humans. However, the efficacy of the approach reported by Vitale et al¹⁷ deserves further research in experimental and especially in human clinical trials to improve immunological treatment modalities of metastatic colon cancer.