Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Diedrich, Jonathan D.; Heath, Elisabeth I.; Podgorski, Izabela

doi:10.1038/s41598-017-17800-5

Cited by 35 publications

(38 citation statements)

References 104 publications

(116 reference statements)

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“…Data showing a close physical association between bone marrow adipocytes and melanoma and breast cancer cells suggest that adipocytes may regulate tumor cells within the bone microenvironment . In support of this, mice on high‐fat diets develop bone marrow adiposity that is associated with increased tumor cell growth and osteolysis in the bone . This phenotype is likely mediated by bone marrow adipocytes, rather than other adipose stores, because direct tumor‐promotional effects of bone marrow adipocytes are observed in vitro, including increased tumor cell proliferation and invasion .…”

Section: Adipocytes: a Role For Fat In Bone Homeostasismentioning

confidence: 90%

Understanding the Bone in Cancer Metastasis

Fornetti

Welm

Stewart

2018

Journal of Bone and Mineral Research

330

225

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The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. (1) Unfortunately, once cancer spreads to the bone, it is rarely cured and is associated with a wide range of morbidities including pain, increased risk of fracture, and hypercalcemia. This fact has driven experts in the fields of bone and cancer biology to study the bone, and has revealed that there is a great deal that each can teach the other. The complexity of the bone was first described in 1889 when Stephen Paget proposed that tumor cells have a proclivity for certain organs, where they "seed" into a friendly "soil" and eventually grow into metastatic lesions. Dr. Paget went on to argue that although many study the "seed" it would be paramount to understand the "soil." Since this original work, significant advances have been made not only in understanding the cell-autonomous mechanisms that drive metastasis, but also alterations which drive changes to the "soil" that allow a tumor cell to thrive. Indeed, it is now clear that the "soil" in different metastatic sites is unique, and thus the mechanisms that allow tumor cells to remain in a dormant or growing state are specific to the organ in question. In the bone, our knowledge of the components that contribute to this fertile "soil" continues to expand, but our understanding of how they impact tumor growth in the bone remains in its infancy. Indeed, we now appreciate that the endosteal niche likely contributes to tumor cell dormancy, and that osteoclasts, osteocytes, and adipocytes can impact tumor cell growth. Here, we discuss the bone microenvironment and how it impacts cancer cell seeding, dormancy, and growth. Fig. 1. Tumor cells closely associate with cells of the bone microenvironment in a mouse model of bone metastasis. Scale bar ¼ 50 mm. Ad ¼ adipocyte; EC ¼ endothelial cell; Oc ¼ osteocyte; Ocl ¼ osteoclast; Tu ¼ tumor.

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Section: Adipocytes: a Role For Fat In Bone Homeostasismentioning

confidence: 90%

Understanding the Bone in Cancer Metastasis

Fornetti

Welm

Stewart

2018

Journal of Bone and Mineral Research

330

225

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“…These cells, present at the invasive front, are likely to metastasize to distant sites, the bone representing the most common location of metastatic disease in prostate cancer. A bidirectional crosstalk also exists between bone marrow adipocytes and prostate cancer cells, promoting tumor progression, which appears to involve different actors such as IL1b and heme oxygenase 1 (19,50). Again, occurrence of different mechanisms is not surprising because bone marrow adipocytes are clearly phenotypically different from classical fat depots such as PPAT (46).…”

Section: Validation Of the Depicted Signaling Pathway In Human Tumorsmentioning

confidence: 99%

Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress

Laurent

Toulet

Attané

et al. 2019

Molecular Cancer Research

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Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. Implications: Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.

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“…Adipocytes exert a critical role in disease progression in the tumour microenvironment by providing cancer cells with fatty acids, pro-inflammatory cytokines, and proteases [13][14][15]. Also, BMAs promote tumour cell oxidative stress [16] and metabolic reprogramming toward a glycolytic phenotype [17]. BMAT is crucial in the development of blood disease, in which BMAs directly interact with blood tumour cells in the bone marrow.…”

Section: Bone Marrow Adipose Tissue (Bmat) the Third Fat Depotmentioning

confidence: 99%

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Maroni

2020

IJMS

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The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

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Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin

Cited by 35 publications

References 104 publications

Understanding the Bone in Cancer Metastasis

Understanding the Bone in Cancer Metastasis

Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

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