A novel leptin antagonist peptide inhibits breast cancer growth <i>in vitro</i> and <i>in vivo</i>

Catalano, Stefania; Leggio, Antonella; Barone, Ines; Marco, Rosaria De; Gelsomino, Luca; Campana, Antonella; Malivindi, Rocco; Panza, Salvatore; Giordano, Cinzia; Liguori, Alessia; Bonofiglio, Daniela; Liguori, Angelo; Andò, Sebastiano

doi:10.1111/jcmm.12517

Cited by 56 publications

(52 citation statements)

References 60 publications

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“…Several peptide antagonists of LEPR (allo-aca, PEG-LPrA2 and LDFI) have been shown independently to be effective against both estrogen receptor positive (MCF7) or negative (MDA-MB-231) breast cancer xenograft models [54–56]. Clinical development of TGFB1 inhibitors is more advanced, with several agents in phase III clinical trials (reviewed in [57]).…”

Section: Discussionmentioning

confidence: 99%

Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer

et al. 2017

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Epidemiological studies have shown obesity to be linked with poorer outcomes in breast cancer patients. The molecular mechanisms responsible for the increased risk of invasive/metastatic disease with obesity are complex, but may include elevated levels of adipokines such as leptin. Using physiological levels of leptin found in obesity in a novel chronic in vitro treatment model (≤200 ng/ml for 14 days), we confirmed the occurrence of leptin-mediated changes in growth, apoptosis and metastatic behavior, and gene expression changes representing epithelial-to-mesenchymal transition (EMT) and a cancer stem cell (CSC) like phenotype in breast epithelial and cancer cell lines (MCF10A, MCF10AT1, MCF7 and MDA-MB-231). Further, we have discovered that these effects were accompanied by increased expression of TGFB1, and could be significantly reduced by co-treatment with neutralizing antibody against TGFB1, indicating that the induction of these characteristics was mediated via TGFB1. Occurring in both MCF7 and MCF10AT1 cells, it suggests these actions of leptin to be independent of estrogen receptor status. 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. Inhibitors of TGFB1 are in currently in phase III clinical trials in other malignancies, thus identifying the connection between leptin and TGFB1 will open new therapeutic opportunities for improving outcomes for obese breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer

et al. 2017

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“…Interestingly, leptin expression in gastric adenocarcinoma cell-lines was reported to be correlated with resistance to the chemotherapeutic agent cisplatin [111]. Furthermore, including a leptin antagonist increased the sensitivity of both the cisplatin-resistant gastric cancer AGS Cis5 and esophageal adenocarcinoma OE33 cell-lines to cisplatin, which greatly illustrated the impact of leptin in the disease course (Table 2 [101,111,112]).…”

Section: Leptin and Tumor Behavior Of The Gastrointestinal Tractmentioning

confidence: 99%

The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

114

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The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. 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. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

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“…LDFI was reported to inhibit leptin-induced growth of breast cancer cells in vitro and in vivo [174]. This peptide antagonist inhibited proliferation, colony formation on soft agar and Boyden chamber transmigration of estrogen receptor positive as well as estrogen receptor negative breast cancer cells.…”

Section: Leptin Antagonists and Cancer Progressionmentioning

confidence: 99%

“…In vivo , the pegylated peptide (LDFI-PEG) was shown to inhibit the tumour growth in a murine mammary xenograft model. LDFI-PEG showed no toxicity or effects on BW of mice[174]. No reports on potential effects of LDFI on drug resistance in breast or other cancer types are available.…”

Section: Leptin Antagonists and Cancer Progressionmentioning

confidence: 99%

Leptin signaling and cancer chemoresistance: Perspectives

Candelaria¹,

Rampoldi²,

Harbuzariu³

et al. 2017

WJCO

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Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.

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A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo

Cited by 56 publications

References 60 publications

Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer

Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer

The potential role of leptin in tumor invasion and metastasis

Leptin signaling and cancer chemoresistance: Perspectives

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