How Useful Are Interferons in Oncology

Interferon Definition

Interferons refer to glycoproteins which are synthesized by different cells in reaction to specific chemical inducers, immune stimulation, and viral infection. Interferon seems to act in a paracrine ability in the immune system, with an extensive range of impacts which imitates the endocrine system diversity. There are currently 20 identified interferons in human, which can only be categorized in three extensive groups. Majority of the subtypes fit in the alpha class, two beta subtypes (1 and 2) have been defined and there is just one species of gamma.

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Both Beta and Alpha interferons were initially named based on their early production methods which include fibroblast-derived beta and leukocyte-derived alpha, though they actually seem to be virtually synthesized by each cell in the body. However, Gamma interferon is a lymphokine that is solely secreted by T cells. There are obvious homologies between human beta and alpha interferons such that they share a surface of cell receptor preset on chromosome 21 and their genes cluster on chromosome 9. On the contrary, their gamma gene is on chromosome 12 and demonstrates no homology with beta and alpha interferons. The receptor is position on chromosome 6 and seems to vary from that of beta and alpha interferons.

Interferons Contribution to Oncogenesis

Interferons can trigger biological signaling pathways plethora in tumor cells which include cell invasion, survival, and differentiation. Interferon can actually impact proliferation of cell in tumor cells by blocking or prolonging the cycle of the cell, regulating CRKL, p38 MAPK, or p21, which consequently interacts with RAP1A; suppressor of a tumor which antagonizes RAS. Interferons can as well control the apoptotic machinery by managing the intrinsic and extrinsic apoptotic pathways. The type I interferon genes deletion and the interferon receptors down-regulation or signaling molecule engaged in the cascade of interferon that include STAT 1 can cause tumor cell to bypass regulatory impacts. This explains the restricted failure of interferon applied to control proliferation of cancer cell in various models.

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Beside the above highlighted direct effects, interferons can also control tumor cell growth indirectly, impacting varying biological process engaged in progression of tumor, that include immunity and angiogenesis. The initial illustration of interferons indirect effect demonstrated that interferons administration enhanced the survival of mice impacted by lymphocytic leukemia, irrespective of intrinsic tumor cells sensibility to IFN preparations. Actually, interferons act as various immune cells activators which include T cells, B cells, NKs, DCs, and macrophages. It has lately been illustrated that DCs creating type I interferons prompt an antitumor effect in mice impacted by melanoma. On the contrary, infiltrating DCs accumulation was related with a poor breast cancer prognosis. These seemingly conflicting outcomes can be explained by recent outcomes that illustrate that deficit of alpha interferons in tumor related DCs amass in aggressive tumors and result to regulatory T cells expansion which contribute to immune tolerance of tumor and a poor clinical results. It has been illustrated that tumor cells normally abrogate production of interferon to successful metastasize. The interferons immunoregulatory effect includes the tumor antigen up-regulation expression, the presentation of the DCs tumor antigen to T cells, the CD8+ T cells effector phenotype acquisition, the T cells down regulation, the myeloid-derived suppressor cells amass inhibition, and differentiation of the monocyte in M1-polarized macrophages of immunostimulatory. In addition, interferons can augment the antigen presentation of the main histocompatinility complex (MHC), the ligands expression engaged in immune checkpoint that include the programmed protein 1 cell death, and the cytokines release. 

Pro-Apoptosis Antitumor Effects of interferons

Apoptosis is an extra mechanism applied to control tissues cell number and eliminate particular cells which threatened the survival of the host. Interferon type I is related with apoptosis brought about by DNA damage or other stimuli. When presented with an activated oncogene, wild-typed MEFs undergo apoptosis rather than arrest of cell cycle when treated with ionizing radiation or anti-cancer drugs. Apoptosis is a tumor suppression hallmark and is dependent on p53 and interferons type I in this case. However apoptosis induced by damage of DNA in mitogenically triggered mature T lymphocyts is reliant on interferon type I though independent of p53.

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The research demonstrates that interferon type I is vital for p53-independent apoptosis promotion in acutely destroyed human mammary basal form of epithelial cell, creating evidence that interferon type 1 loss is a short-term indicator of early risk of basal-form of breast cancer. The research indicates that interferon type 1 protein ectopic expression yields to surviving protein downregulation expression which is p53 independent and enhance death of breast cancer cell.

Immune Antitumor Effects of interferons

Type I interferons are acknowledged for mediating effects of antineoplastic over a number of malignancies that is clinically significant activity which has been accredited to their immune-stimulatory roles. Experimental data strongly propose the existence of a process in which the immune system in the external manipulation absence safeguards the host over oncogenesis and manages the developing tumor immunological features. The process that is regarded as cancer immunoediting contains three phases.

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In the first phase involves malignant cells elimination through immune system. In the second phase the equilibrium establishment between the immune system and unstable malignant cells that reflects the immunoediting imposed on cancer cells by the immune system. In the third phase the variants of neoplastic cell escape with minimized immunogenicity that eventually form neoplasms which are clinically manifested. The interferons type I intervene in all the three faces.

Inhibition of Metastasis Antitumor Effects of interferons

Interferons is also said to play a vital role in inhibiting tumor metastasis in nasopharyngeal carcinoma (NPC) which is frequently metastasized and highly malignant tumor, with very poor prognosis when distant metastases take place. The alpha and beta interferons antitumor effects were examined on NPC. The outcome demonstrated that recombinant human alpha and beta interferon suppress growth of cell, induced cell cycle of G1-phase arrest in vitro augmented the pRb and p16 expression, and reduced the CDK6 and CCCNDI expression. In vivo analysis demonstrated that either beta and alpha 1 interferon or recombinant adeno-related virus alpha 1 and beta virus treatment inhibited tumor metastasis and growth, lowered microvessel density of intratumoral, increased cell necrosis and apoptosis and induced elongated survival. The research proposed that alpha I and beta interferon acts as a multipurpose antitumor agent in NPC that might contain significant therapeutic implications.  

Inhibition of Angiogenesis Antitumor Effects of interferons

Interferon gamma has been said play a vital role in suppressing tumor angiogenesis. Interferon gamma secreted by both NK cells and NKT cells plays an essential role in facilitating the alpha-galactosylceramide effect. The research shows that tumor angiogenesis inhibition by interferon gamma induced by alpha-galactosylceramide (α-GakCer). Mice with tumor induced angiogenesis and subcutaneous tumor were treated using α-GakCer where the growth of the tumors were inhibited in interferon gamma dependent way. This proposed that interferon gamma mediated tumor angiogenesis inhibition is critically engaged in the antitumor effects effector mechanism initiated by α-GakCer.

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