Role of Leptin in Cancer: A Systematic Review

Leptin has been referred to one of the satiety hormones. Leptin is a peptide hormone contains 167 amino acids, 16kDa protein encoded by LEP qualities that delivered by adipocytes and has part in keeping up vitality adjust. It is a protein hormone that expressions in the hypothalamus decline the adiposity. It is different in their activity that is the reason additionally called as pleiotropic hormone [1]. It assumes imperative part in both natural resistance and versatile invulnerability. Leptin-lacking individuals have weakened insusceptibility. It influences cytotoxicity of NKs; now and again it has cytotoxicity-decreasing impact and in some cases, it improves the cytotoxicity [2]. Several studies on cancer incidence link the predisposition to develop certain types of cancers (e.g. colon, thyroid, esophagus, pancreatic, endometrial, and postmenopausal breast cancer) with an individual’s excess body mass/obesity [2]. Leptin is widely studied factor both in general metabolism and in obesity related cancers [3]. Leptin may balance diverse components in a few frameworks, for example, actuating or hindering the progressing steps of the disorders, and the learning of the relationship amongst obesity and cancer makes leptin an examination focus for different sorts of cancers [4].


Introduction
Leptin has been referred to one of the satiety hormones.
Leptin is a peptide hormone contains 167 amino acids, 16kDa protein encoded by LEP qualities that delivered by adipocytes and has part in keeping up vitality adjust. It is a protein hormone that expressions in the hypothalamus decline the adiposity. It is different in their activity that is the reason additionally called as pleiotropic hormone [1]. It assumes imperative part in both natural resistance and versatile invulnerability. Leptin-lacking individuals have weakened insusceptibility. It influences cytotoxicity of NKs; now and again it has cytotoxicity-decreasing impact and in some cases, it improves the cytotoxicity [2]. Several studies on cancer incidence link the predisposition to develop certain types of cancers (e.g. colon, thyroid, esophagus, pancreatic, endometrial, and postmenopausal breast cancer) with an individual's excess body mass/obesity [2]. Leptin is widely studied factor both in general metabolism and in obesity related cancers [3]. Leptin may balance diverse components in a few frameworks, for example, actuating or hindering the progressing steps of the disorders, and the learning of the relationship amongst obesity and cancer makes leptin an examination focus for different sorts of cancers [4].
Leptin, a cytokine that is hoisted in obese people, and cancer progression [5]. While the effect of overabundance body weight, the connection amongst obesity and carcinogenesis is simply being perceived. The component of fat tissue-actuated growth is not known, but rather a few conceivable situations can be imagined. On account of hormone-dependent neoplasms such as breast cancer; increased production of growth factor and secretion of estrogenic compounds, insulin/IGF pathways, angiogenic stimulators by excess fat tissue could subsidize to tumor growth and metastasis [6]. Our aim is to identify and review those studies that have been investigated the role of leptin in different malignancies/ cancers. Currently a lot of work is being done on leptin because it is involved in multiple complex disorders; a thorough understanding of its pathways can provide opportunities to diagnose and treat disorders. Several signaling pathways then can act as therapeutic targets to cure diseases i.e. cancer. The following questions were addressed in this study: a) What's the reason leptin is considered so important?

Study Selection
All broad, peer-explored literature is incorporated and was viewed as reasonable for consideration. The examination confirms identifying with relationship of leptin with autoimmunity issue, cardiovascular maladies is a far from the point of our study.

Data Extraction
Material withdrawal was conducted utilizing systematize format made for the review and each article was assessed by two analysts. The information uprooting was affirmed for its intactness and validity by analyst. The accompanying information was separated: Leptin, impacts of leptin, hormonal secretion and immunity, finding on association of leptin with various cancer, role of angiogenesis and treatment of cancer.

Data Synthesis
Information was sorted out as indicated by type of cancer that is regulated by leptin.   in the salvage pathway [9]. NAMPT has also been reported to be a cytokine PBEF that promotes B cell maturation and inhibits neutrophil apoptosis [10]. Diagrammatic illustration of intracellular signaling pathway by leptin is as shown in Figure 1.

Role of Leptin in Cancer
Disease propagation is a multistep procedure including different strides, for example, start of tumor, essential tumor development, intrusion, and metastatic movement which includes complex connection with different stromal parts including endothelial cells, insusceptible cells, fibroblasts, and adipocytes [11]. Leptin bind to its receptor Ob-R, a product of the Ob gene, to apply its impact [12]. Leptin and its receptors both are missing in ordinary epithelial breast tissue however over-expressed in cancer particularly in breast malignant cell and, represent a poor prognostic factor, related to the presence of remote metastasis and short survival [12][13][14]. Through an autocrine mechanism leptin is mainly concerned in incitement of estrogen dependent breast cancer [15,16] [40][41][42], renal cell carcinoma [43], and leukemia [44,45], and additionally colorectal tumor it indicates cancer patient have smaller adiponectin level [46]. It actuates AMP-activated protein kinase (AMPK), fortifies unsaturated fat oxidation, enhances insulin affectability and glucose digestion [47], goes about as a direct endogenous inhibitor of inflammation and angiogenesis, and diminishes tumor intrusiveness [48][49][50].  [51]. Tumor tissues required oxygen and nutrients for rapidly growing, so in order to supply nutrient angiogenesis (major factor of caner spread) is stimulated. So, the outburst of tumor cells reflect the expression of angiogenic factors [52]. Leptin become the cause of over expression of vascular endothelial growth factor (VEGF) that ultimately promote the growth of mammary atumor [53]. Leptin act as angiogenesis inducer that lead to formation of 3D capillary like tubes, vascular endothelial growth factor (VEGF) also lead this. VEGF165 is supported by leptin considered as a major proangiogenic factor just like endothelial growth factor [54]. The appearance of the VEGF family in tumor cells and nearby stroma is depend upon growth factors like cytokines, once VEGF family appear it involved in neovascularization [55]. Neovascularization and it proliferate through JAK/STAT and AKT mechanism in a matrigel invasion assay [58]. The mechanism through which leptin promote angiogenesis in pathological and physiological conditions as demonstrated in figure [59]. Angiogenesis causes these cancers through VEGF pathway activated by leptin [52] (Figure 2).

Figure 2:
Leptin secreted by adipocytes increase VEGF, that cause vascular permeability that lead to angiogenesis through vascular fenestration, leptin binds to it receptor and increase that again increase cytokines that lead to angiogenesis.   This hormone presumably through its receptor and enactment of the PI3K/AKT pathway assumes a vital part in papillary thyroid tumor pathogenesis [69]. It additionally appears that the oncogenic impacts of leptin on papillary thyroid carcinoma cells are identified with the invigorating cell multiplication and inhibit apoptosis [70].

Role of Leptin in Breast
Pathway has been illustrated in figure 5 [31].

Figure 5:
Leptin/Ob-Rb restricting outcomes in insulin receptor substrate (IRS) phosphorylation, which thusly activates PI3K/ AKT pathway through the relationship of IRS with the administrative subunit p85 of AKT. Actuated AKT thusly phosphorylates XIAP (an individual from antiapoptotic proteins) hence inhibiting its degradation, which prompts diminished caspase-3 action and diminished apoptosis.

Role of Leptin In Pancreatic Cancer: Pancreatic cancer (PC)
is the fourth major case of cancer death in Western countries [71].
Among 80% of all pancreatic cancer, the most important malignancy is pancreatic adenocarcinoma [71,72]. The several bioactive adipokines recognize active endocrine organs by adiopose tissue which carryout many pathological and physiological processes like insulin resistance and sensitivity, appetite, immunity, hematopoiesis and angiogenesis. Leptin and adiponectin are two important adipokines [73,74]. The insulin resistance relates with low level of leptin whereas insulin-sensitizing, anti-inflammatory and anti-atherogenic adipokines relates with low level of adiponectin have protective role in malignancies of several types [75]. Leptin promotes vascularization, proliferation, migration and invasion of tumor cells. Obesity promotes pancreatic carcinogenesis and increase leptin concentration [76]. Obesity also changes other adipokines and growth factor, fatty infiltration of pancreas, high leptin level in pancreatic tissues, 2-folds higher serum leptin concentration and noticeable increase in number of pancreatic tumors ( Figure 5). Serum leptin is more sensitive marker for intra-abdominal or visceral adiposity which relates with body mass index [77].  CD107 and NK action [82]. An expanded articulation of perforin, TRAIL and IFN-γ express on NK cell, on administration of leptin to NK cell that enhance cytotoxic activity [82][83][84].

Leptin and Natural
Diminished IFN-γ generation and cytotoxity against tumor cell occur on incubation of NK with leptin for longer time and higher concentration for example incubation in 10ng/ml for 3-4 day or 100ng/ml for 1-2 day [83][84][85] It means typical level of leptin is needed for NK effector system, with brief increment in leptin NK activity increase, but long term administration suppress NK activity [79]. The cells that are resistant against TRAIL and Fas-L require other mechanism for their lysis i-e using receptor of NK cell such as NKp30, NKp46 and NKG2D. These receptors are regulated by leptin. Blocking of these receptors decreases the cytotoxic activity [84]. In cancer patient NK cell lose their ability to kill cancer cell. To overcome this problem or for killing the cancer cell, there is a need to activate the NK and its function. Level of leptin increased during cancer. Leptin can be used to regulate the NK activity as shown in Table 1.

Leptin Level Secretions of Natural Killer Regulation of Effectors by Leptin Mechanism Through Which NK Involve in Cancer Therapy References
Normal level Perforin Administration of leptin to NK cell increases expression of perforin and granzyme and its cytotoxic action.
Granule exocytosis pathway: When NK cell interacts with cancer cell, cytotoxic granules (perforin and granzyme) release from NK cell. Perforin interacts with cell membrane and forms a pore on the surface of target cell for the entry of granzyme. This granzyme activates apoptosis of cancer cell. Receptor of FAS and TRAIL (tumor-necrosis-factorrelated apoptosis-inducing ligand) is present on cancer cell it binds with ligand of FAS and TRAIL (present on the surface of NK cell). On interaction it forms a complex to activate NK cell and to release signal that mediate apoptosis of cancer cell.

IFNγ
Administration of leptin to NK cell increases production of IL-2 and IL-15 that enhance release of IFNγ IFNγ activates T-cell and mediates apoptosis through Jak and STAT signaling.

High level of leptin for long time
Administration of leptin to NK cell increases production of TRAIL and IFNγ above the normal level High level of TRAIL and IFNγ shows toxic effect against normal cell instead of cancer cell. [79] High or low level of leptin for short or long time respectively Incubation of NK in leptin 100ng/ ml for 1-2 day or 10ng/ml for 3-4 day.
Diminished IFN-γ generation and cytotoxity against tumor cell.

Conclusion
There is a consistent confirmation that leptin is related with immunity, cause cancer and other autoimmune diseases. High level of leptin expands articulation of anti-apoptotic proteins, TNF-α and angiogenic factor which promotes cancer cell survival and