The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis

Shin, Eunah; Koo, Ja Seung

doi:10.3390/ijms21144967

Cited by 27 publications

(23 citation statements)

References 190 publications

(209 reference statements)

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“…This was more evident with the ER+/HER2-subtype compared with TNBC, which indicates that the role of adipocytes is more significant with the ER+/HER2-subtype. Our result is in perfect alignment with the previous studies that leptin, one of the well-known adipokines which enhances the cell proliferation and metastasis [53,54], and leptin receptor signaling crosstalk with ER signal pathway in ER+ subtypes but not in ER-subtypes [55,56].…”

Section: Discussionsupporting

confidence: 92%

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

Tokumaru

Oshi

Katsuta

et al. 2020

IJMS

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Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

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Section: Discussionsupporting

confidence: 92%

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

Tokumaru

Oshi

Katsuta

et al. 2020

IJMS

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“…Upon obesity, the number of bone marrow adipocytes increases [ 112 ]. Adipokines mediate several protumorigenic effects on cancer cells, including promotion of survival, growth, invasion, migration, and metastasis, as well as the recruitment of immune cells and mediation of chemoresistance [ 110 , 113 , 114 ].…”

Section: Impact Of Inflammation On Cancer Metastases To Bonementioning

confidence: 99%

“…Moreover, obesity is associated with the increased production of CCL2 and cyclooxygenase-2 (COX-2) within the bone marrow, factors which, in turn, exert protumorigenic and proosteoclastic effects [ 108 ]. The production of COX-2 by bone marrow adipocytes promotes osteolysis and is involved in evasion mechanism of tumor cells by creating an immune suppressive milieu [ 113 ]. PrCa and BrCa cells incorporate adipocyte-derived factors such as fatty acids which support tumor growth and invasion.…”

Section: Impact Of Inflammation On Cancer Metastases To Bonementioning

confidence: 99%

“…Moreover, adipocyte-derived chemotactic CXCL1 and CXCL2, ligands of the CXCR2 receptor, stimulate macrophage recruitment and osteoclastogenesis, thus sustaining the intraosseous vicious cycle [ 108 , 123 ]. Hence, several inhibitors of adipokines are currently investigated in clinical and preclinical trials for their anti-tumor effects as well as their potential to suppress bone metastasis [ 113 ].…”

Section: Impact Of Inflammation On Cancer Metastases To Bonementioning

confidence: 99%

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The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone

Göbel

Dell'Endice

Jaschke

et al. 2021

IJMS

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Tumor metastasis to bone is a common event in multiple forms of malignancy. Inflammation holds essential functions in homeostasis as a defense mechanism against infections and is a strategy to repair injured tissue and to adapt to stress conditions. However, exaggerated and/or persistent (chronic) inflammation may eventually become maladaptive and evoke diseases such as autoimmunity, diabetes, inflammatory tissue damage, fibrosis, and cancer. In fact, inflammation is now considered a hallmark of malignancy with prognostic relevance. Emerging studies have revealed a central involvement of inflammation in several steps of the metastatic cascade of bone-homing tumor cells through supporting their survival, migration, invasion, and growth. The mechanisms by which inflammation favors these steps involve activation of epithelial-to-mesenchymal transition (EMT), chemokine-mediated homing of tumor cells, local activation of osteoclastogenesis, and a positive feedback amplification of the protumorigenic inflammation loop between tumor and resident cells. In this review, we summarize established and evolving concepts of inflammation-driven tumorigenesis, with a special focus on bone metastasis.

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“…Consistently, transgenic mice expressing human IL-8 demonstrated an osteopenic phenotype with elevated bone resorption [ 47 ]. Another striking finding in this mouse model was the increase in marrow adiposity as marrow adipocytes and associated adipokines are known to contribute to breast cancer bone metastasis [ 8 , 117 ]. In vitro studies have reported the secretion of two different isoforms of IL-8 by breast cancer cells, both being able to stimulate osteoclastogenesis [ 47 ].…”

Section: The Role Of Ils During the Establishment And Progression mentioning

confidence: 99%

Interleukins as Mediators of the Tumor Cell—Bone Cell Crosstalk during the Initiation of Breast Cancer Bone Metastasis

Haider

Ridlmaier

Smit

et al. 2021

IJMS

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Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for these patients. Bone is among the most frequent sites of metastasis in breast cancer. Once in the bone, disseminated tumor cells can acquire a dormant state and remain quiescent until they resume growth, resulting in overt metastasis. At this stage the disease is characterized by excessive, osteoclast-mediated osteolysis. Cells of the bone microenvironment including osteoclasts, osteoblasts and endothelial cells contribute to the initiation and progression of breast cancer bone metastasis. Direct cell-to-cell contact as well as soluble factors regulate the crosstalk between disseminated breast cancer cells and bone cells. In this complex signaling network interleukins (ILs) have been identified as key regulators since both, cancer cells and bone cells secrete ILs and express corresponding receptors. ILs regulate differentiation and function of bone cells, with several ILs being reported to act pro-osteoclastogenic. Consistently, the expression level of ILs (e.g., in serum) has been associated with poor prognosis in breast cancer. In this review we discuss the role of the most extensively investigated ILs during the establishment of breast cancer bone metastasis and highlight their potential as therapeutic targets in preventing metastatic outgrowth in bone.

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The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis

Cited by 27 publications

References 190 publications

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

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

The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone

Interleukins as Mediators of the Tumor Cell—Bone Cell Crosstalk during the Initiation of Breast Cancer Bone Metastasis

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