Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis.
Leptin is an adipokine that is significantly increased in obese patients and that functions in various biological processes of cancer, such as tumor growth and metastasis.
Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER⁺) breast cancer (BC) tumor growth and metastasis.
Furthermore, 5-FU combined with LEP-2a also resulted in p53 activation and NF-κB inhibition, and cell cycle arrest in the S phase as well as cell metastasis stagnation.
Leptin produced by obesity-altered adipose stem cells promotes metastasis but not tumorigenesis of triple-negative breast cancer in orthotopic xenograft and patient-derived xenograft models.
To do so, leptin binds to its receptor (OB-Rb) to activate signaling pathways and downstream effectors that participate in tumor cell invasion as well as distant metastasis.
Thus, immunohistochemical staining of leptin in colorectal cancer could be a helpful tool in the prediction of prognosis and survival pattern of colorectal cancer with certain clinicopathological factors (tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease).
Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays.
Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis.
By linking leptin signalling to the established TGFB1 pathway of metastasis / EMT, this study gives a direct mechanism by which leptin can contribute to the poorer outcomes of obese cancer patients.
Since IRS1/2 interact with and transmits signals from the receptors of insulin, Insulin Like Growth Factor 1 (IGF1), prolactin, growth hormone (GH), leptin, Vascular Endothelial Growth Factor (VEGF), TrkB, ALK and integrins this promoted scientist to think that IRS1 may have functions in cell proliferation, tumorigenesis and metastasis.
Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination.
The present meta-analysis suggests that the serum and tissue leptin may be involved in the pathogenesis of lung cancer and tumor metastasis, especially among Chinese.
Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay.
We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients.
This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women.
In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis.
High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer.