Obesity, Adipokines and Cancer: An Update
Obesity, Adipokines and Cancer: An Update
Leptin, the product of the Obese (OB) gene, is an adipokine primarily secreted by white adipose tissue. In addition to its key role in energy homoeostasis as a satiety hormone, leptin also exerts other effects in an endocrine fashion. In the context of obesity, leptin level increases with the expansion of the adipose tissue mass. In humans, obesity is associated with leptin resistance, further increasing the circulating leptin level. By binding to its receptors (Ob-R), which are expressed in almost every tissue, leptin modulates various downstream signalling pathways (Fig. 1) including JAK/STAT3, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), ERK1/2, AMPK and insulin receptor substrate (IRS) pathways. In contrast to the anti-inflammatory actions of adiponectin, leptin activates inflammatory cell response and induces pro-inflammatory cytokine production. Furthermore, in vitro studies demonstrated that leptin could induce endothelial cell proliferation and activate vascular endothelial growth factor (VEGF), and other proangiogenic factors. These resultant effects make leptin an adipokine with mitogenic, anti-apoptotic and pro-inflammatory properties, all being implicated in carcinogenesis. Table 2 summarizes the role of leptin in various obesity-related cancers.
As in adiponectin, the association between leptin and breast cancer also seems to depend on menopausal status. While there is consistent evidence showing that serum leptin level correlates positively with breast cancer risk in postmenopausal women, an inverse relationship has been reported in premenopausal subjects. Nonetheless, previous in vitro studies had already demonstrated that leptin promoted mammary tumourigenesis via activation of JAK/STAT3 and PI3K signalling pathways. Leptin has also been shown to affect the prognosis of breast cancer. Leptin-receptor-positive tumours had higher metastatic potential than those that were negative for leptin receptor. A recent study confirmed that leptin stimulated proliferation of breast cancer cells but not of normal breast cells. In particular, leptin-induced proliferation of oestrogen-dependent breast cancer cell lines such as MCF7 and T47D but not of the oestrogen-independent breast cancer cell lines MDA-MB-231. In fact, functional bidirectional crosstalk had been demonstrated between leptin and oestrogen receptors. Leptin could amplify oestrogen signalling by activation of oestrogen receptor-α and aromatase gene (CYP192A) expression. Oestradiol, on the other hand, could modulate leptin-receptor expression in animal studies and also induced expression of leptin and its receptor in MCF7 breast cancer cells. The effect of leptin on oestrogen-independent breast cancers, however, has remained controversial. A study by Colbert et al. in 67 Chinese patients with breast cancer demonstrated that more than 61% of breast cancer tissues, which included oestrogen receptor positive, oestrogen receptor negative and triple (oestrogen, progesterone and HER2 receptors) negative tumours, were stained positive for leptin and its receptor. Furthermore, leptin and its receptor were positively associated with proangiogenic factors such as Notch and vascular endothelial growth factor (VEGF) and hence implicated in tumour aggressiveness and poorer prognosis.
Data on the association between leptin and prostate cancer have also been conflicting. Some studies suggested that higher leptin levels were linked to more advanced and hormone-refractory prostate cancer.In vitro studies demonstrated that leptin exerted its pro-carcinogenic effects via the activation of PI3K, MAPK and JNK-MAP kinase pathways. Leptin could induce proliferation, inhibit apoptosis and promote the migration of androgen-insensitive prostate cell lines DU145 and PC3 but did not have an effect on the androgen-sensitive cell line LNCaP.
Although leptin was linked with colorectal cancer risks in multiple epidemiological studies, a recent meta-analysis did not observe any significant association between leptin and colorectal carcinoma. Nonetheless, animal studies had shown that leptin-deficient mice were less prone to colonic polyp formation upon induction by azoxymethane or when fed with a high fat diet, when compared to control mice. Furthermore, leptin could stimulate the proliferation of the human colorectal cancer cell line HCT-116 via the PI3K-AKT signalling pathway. Recently, leptin was shown to induce the proliferation of gastric cancer cells through activation of STAT3 and ERK1/2.
On the contrary, although studies on the association between leptin and pancreatic cancer are scarce, most of them showed that leptin levels were lower in patients with pancreatic cancer than in controls. While some had attributed the hypoleptinaemia to the weight loss that was commonly observed in patients with pancreatic cancer, a recent study suggested that patients with newly diagnosed pancreatic cancer had significantly lower serum leptin levels and these differences were independent of age and BMI.In vitro studies also showed that leptin could inhibit human pancreatic cancer cell lines PANC-1 and Mia-PaCa.
A recent prospective cohort study involving 167 incident endometrial cancer cases demonstrated that, as in the case of adiponectin, the association between leptin and endometrial cancer risk also depended upon the use of menopausal hormonal therapy. Leptin was significantly associated with increased risk of endometrial cancer, even after adjustment for oestradiol level and BMI. However, this was only observed in women not on menopausal hormonal therapy, suggesting that leptin might also influence cancer risk through mechanisms other than oestrogen-mediated endometrial proliferation.
The association between leptin and renal cell carcinoma has remained inconclusive over the years. A recent report observed that higher leptin levels were found in patients with renal cell carcinoma, which, though attenuated, remained significant after adjustment for BMI. However, this association was shown to differ by race, as it was significant in Caucasians but not among African Americans.
In differentiated thyroid cancers, the expression of leptin and its receptor was associated with a higher risk of lymph node metastases. Moreover, leptin could affect the migration of thyroid cells, conferring higher metastatic potential and worse prognosis. In the context of haematological malignancies, however, no positive associations were reported between leptin levels and multiple myeloma or non-Hodgkin lymphoma.
Recently, there have been more studies looking into the association between leptin and malignant melanoma. Leptin was found not only to correlate positively with the risk of developing malignant melanoma, but also accelerate tumour growth. Interestingly, it has been proposed that serum leptin-receptor levels might possibly be employed as a new tumour marker of malignant melanoma as its levels are inversely associated with the stage of the disease, with highest levels found at the in situ stage and lowest at stage IV.
Leptin
Leptin, the product of the Obese (OB) gene, is an adipokine primarily secreted by white adipose tissue. In addition to its key role in energy homoeostasis as a satiety hormone, leptin also exerts other effects in an endocrine fashion. In the context of obesity, leptin level increases with the expansion of the adipose tissue mass. In humans, obesity is associated with leptin resistance, further increasing the circulating leptin level. By binding to its receptors (Ob-R), which are expressed in almost every tissue, leptin modulates various downstream signalling pathways (Fig. 1) including JAK/STAT3, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), ERK1/2, AMPK and insulin receptor substrate (IRS) pathways. In contrast to the anti-inflammatory actions of adiponectin, leptin activates inflammatory cell response and induces pro-inflammatory cytokine production. Furthermore, in vitro studies demonstrated that leptin could induce endothelial cell proliferation and activate vascular endothelial growth factor (VEGF), and other proangiogenic factors. These resultant effects make leptin an adipokine with mitogenic, anti-apoptotic and pro-inflammatory properties, all being implicated in carcinogenesis. Table 2 summarizes the role of leptin in various obesity-related cancers.
Leptin and Breast Cancer
As in adiponectin, the association between leptin and breast cancer also seems to depend on menopausal status. While there is consistent evidence showing that serum leptin level correlates positively with breast cancer risk in postmenopausal women, an inverse relationship has been reported in premenopausal subjects. Nonetheless, previous in vitro studies had already demonstrated that leptin promoted mammary tumourigenesis via activation of JAK/STAT3 and PI3K signalling pathways. Leptin has also been shown to affect the prognosis of breast cancer. Leptin-receptor-positive tumours had higher metastatic potential than those that were negative for leptin receptor. A recent study confirmed that leptin stimulated proliferation of breast cancer cells but not of normal breast cells. In particular, leptin-induced proliferation of oestrogen-dependent breast cancer cell lines such as MCF7 and T47D but not of the oestrogen-independent breast cancer cell lines MDA-MB-231. In fact, functional bidirectional crosstalk had been demonstrated between leptin and oestrogen receptors. Leptin could amplify oestrogen signalling by activation of oestrogen receptor-α and aromatase gene (CYP192A) expression. Oestradiol, on the other hand, could modulate leptin-receptor expression in animal studies and also induced expression of leptin and its receptor in MCF7 breast cancer cells. The effect of leptin on oestrogen-independent breast cancers, however, has remained controversial. A study by Colbert et al. in 67 Chinese patients with breast cancer demonstrated that more than 61% of breast cancer tissues, which included oestrogen receptor positive, oestrogen receptor negative and triple (oestrogen, progesterone and HER2 receptors) negative tumours, were stained positive for leptin and its receptor. Furthermore, leptin and its receptor were positively associated with proangiogenic factors such as Notch and vascular endothelial growth factor (VEGF) and hence implicated in tumour aggressiveness and poorer prognosis.
Leptin and Prostate Cancer
Data on the association between leptin and prostate cancer have also been conflicting. Some studies suggested that higher leptin levels were linked to more advanced and hormone-refractory prostate cancer.In vitro studies demonstrated that leptin exerted its pro-carcinogenic effects via the activation of PI3K, MAPK and JNK-MAP kinase pathways. Leptin could induce proliferation, inhibit apoptosis and promote the migration of androgen-insensitive prostate cell lines DU145 and PC3 but did not have an effect on the androgen-sensitive cell line LNCaP.
Leptin and Gastrointestinal Cancers
Although leptin was linked with colorectal cancer risks in multiple epidemiological studies, a recent meta-analysis did not observe any significant association between leptin and colorectal carcinoma. Nonetheless, animal studies had shown that leptin-deficient mice were less prone to colonic polyp formation upon induction by azoxymethane or when fed with a high fat diet, when compared to control mice. Furthermore, leptin could stimulate the proliferation of the human colorectal cancer cell line HCT-116 via the PI3K-AKT signalling pathway. Recently, leptin was shown to induce the proliferation of gastric cancer cells through activation of STAT3 and ERK1/2.
On the contrary, although studies on the association between leptin and pancreatic cancer are scarce, most of them showed that leptin levels were lower in patients with pancreatic cancer than in controls. While some had attributed the hypoleptinaemia to the weight loss that was commonly observed in patients with pancreatic cancer, a recent study suggested that patients with newly diagnosed pancreatic cancer had significantly lower serum leptin levels and these differences were independent of age and BMI.In vitro studies also showed that leptin could inhibit human pancreatic cancer cell lines PANC-1 and Mia-PaCa.
Leptin and Other Cancers
A recent prospective cohort study involving 167 incident endometrial cancer cases demonstrated that, as in the case of adiponectin, the association between leptin and endometrial cancer risk also depended upon the use of menopausal hormonal therapy. Leptin was significantly associated with increased risk of endometrial cancer, even after adjustment for oestradiol level and BMI. However, this was only observed in women not on menopausal hormonal therapy, suggesting that leptin might also influence cancer risk through mechanisms other than oestrogen-mediated endometrial proliferation.
The association between leptin and renal cell carcinoma has remained inconclusive over the years. A recent report observed that higher leptin levels were found in patients with renal cell carcinoma, which, though attenuated, remained significant after adjustment for BMI. However, this association was shown to differ by race, as it was significant in Caucasians but not among African Americans.
In differentiated thyroid cancers, the expression of leptin and its receptor was associated with a higher risk of lymph node metastases. Moreover, leptin could affect the migration of thyroid cells, conferring higher metastatic potential and worse prognosis. In the context of haematological malignancies, however, no positive associations were reported between leptin levels and multiple myeloma or non-Hodgkin lymphoma.
Recently, there have been more studies looking into the association between leptin and malignant melanoma. Leptin was found not only to correlate positively with the risk of developing malignant melanoma, but also accelerate tumour growth. Interestingly, it has been proposed that serum leptin-receptor levels might possibly be employed as a new tumour marker of malignant melanoma as its levels are inversely associated with the stage of the disease, with highest levels found at the in situ stage and lowest at stage IV.