Tumor-related interleukins: old validated targets for new anti-cancer drug development
Setrerrahmane and Xu Molecular Cancer
Tumor-related interleukins: old validated targets for new anti-cancer drug development
Sarra Setrerrahmane 1
Hanmei Xu 0 1
0 State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University , Nanjing, Jiangsu 210009 , People's Republic of China
1 The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University , Nanjing, Jiangsu 210009 , People's Republic of China
In-depth knowledge of cancer molecular and cellular mechanisms have revealed a strong regulation of cancer development and progression by the inflammation which orchestrates the tumor microenvironment. Immune cells, residents or recruited, in the inflammation milieu can have rather contrasting effects during cancer development. Accumulated clinical and experimental data support the notion that acute inflammation could exert an immunoprotective effect leading to tumor eradication. However, chronic immune response promotes tumor growth and invasion. These reactions are mediated by soluble mediators or cytokines produced by either host immune cells or tumor cells themselves. Herein, we provide an overview of the current understanding of the role of the best-validated cytokines involved in tumor progression, IL-1, IL-4 and IL-6; in addition to IL-2 cytokines family, which is known to promote tumor eradication by immune cells. Furthermore, we summarize the clinical attempts to block or bolster the effect of these tumor-related interleukins in anti-cancer therapy development.
Cancer; Tumor microenvironment; Immune cells; Cytokines; Anti-cancer
Background
Early in 1863, Virchow postulated cancer proliferation at
sites of chronic inflammation and infection. His
conclusion was based, in part, on the hypothesis that some
classes of mediators causing the inflammation can enhance
tumor cells proliferation, in another part on the evidences
revealing the presence of leukocytes in neoplastic tissue
[
1
]. Several experimental and epidemiological data came
to support this contention. Examples include increased
incidence of virus-associated cancers, liver and pancreas
cancer caused by alcohol induced inflammation and
smoking- related lung inflammation and carcinoma [
2–5
].
Other data suggested that sporadic or inherited genetic
mutations in some critical genes regulating cell cycle,
programmed cell death or differentiation and adhesion might
be the actual cause of tumorigenesis. Chronic
inflammation and cytokines production favor selection of additional
features in initiated cells, which may be the promotor of
malignant transition [
6, 7
].
The tumor microenvironment is rich in a variety of
immune cells, composed of both myeloid (innate
immunity) and lymphoid (adaptive immunity) lineages [
8–
10
]. The former involves macrophages, granulocytes,
mast cells, dendritic cells (DCs), and natural killer (NK)
cells. Contrary to what was thought, not all these
leukocytes represent an attempt by the host to eradicate
transformed neoplastic cells. Only some are [
11
], and all
other classes may support tumor growth, invasion,
metastasis, and escape from the host immune response and
conventional anti-cancer therapy [
12, 13
]. On the other
hand, adaptive immunity is generally represented by B
and T lymphocytes. Acute activation of B cells may play
a role in eradicating early neoplastic cells, or inducing
tumor regression via the secretion of antigen-specific
immunoglobulins [14]; meanwhile, the chronic
activation of B cells may paradoxically play a role in
potentiating cancer development. Moreover, cytotoxic T
lymphocytes (CTLs) recruited in acute tumor-directed
immune responses, appear to protect against tumor
development [
15, 16
], whereas the immune responses
involving chronic activation of humoral immunity and
infiltration of Th2 cells, result in the promotion of
tumor development and disease progression [16]. As
shown in Fig. 1, the regulation of such immune
responses is mediated by the cytokines secreted to initiate
or to weaken the host antitumor immunity, [
17, 18
] .
In chronic inflammation, tissue homeostasis is
dramatically perturbed. Tissue-resident macrophages and mast
cells locally secrete soluble factors such as cytokines,
chemokines, bioactive mediators, and matrix-remodeling
proteins that recruit additional leukocytes from the
circulation into damaged area [
19
], this contributes to the
development of most human solid tumors. Recently, a
growing body of literature claimed that cytokines are
not only produced by the immune cells present in the
tumor microenvironment, the autocrine origin of some
inflammatory cytokines, especially IL-1, IL-4 and IL-6,
was observed in large range of solid tumors [
20–22
].
Cancer cells not only express the cytokine, but also over
expresses the related receptor to use it and escape from
the immune response [
23, 24
]. The secreted molecules
could also serve as messengers in the cross ta (...truncated)