Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer

Abstract

It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.

The Importance of Breast Adipose Tissue in Breast Cancer

“…If body fat is extremely low, it affects leptin levels and in turn the menstruation cycle resulting in poor egg quality [98], which underlines the importance of leptin in women's physiology. However, an increasing amount of data suggests a role for leptin in female cancers including breast, cervical, endometrial and ovarian [99]. The effect of leptin expression and its association with BC differs between premenopausal and postmenopausal women.…”

Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

“…In addition, cancer-associated adipocytes secrete chemokines such as Chemokine (C-C motif) ligand 2 (CCL2), which activates NOTCH1 signaling pathway and induces the stemness of the cancer cells [22,33]. Leptin, which is also produced by cancer-associated adipocytes, collaborates with IL-1, and promotes angiogenesis by upregulating expression of VEGF and VEGF receptors [22,[34][35][36].…”

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

“…Growing evidence indicates that the adipokine leptin, a pleiotropic molecule encoded by the obese gene originally known for its role as a regulator of food intake and energy balance in the mammalian central nervous system, plays a crucial role in maintaining cancer in a stem-like state. Indeed, the expression of the leptin receptor (ObR) is a feature of cancer stem cells and its activation is able to regulate several signaling pathways and oncogenes, which are critically implicated in cancer stem cell activity [ 8 , 9 ]. It has been found that human GBM cell lines as well as human primary GBM tissues expressed leptin along with its receptor and their levels correlate with the degree of malignancy [ 10 , 11 , 12 , 13 ].…”