White Adipose Tissue Cells Are Recruited by Experimental Tumors and Promote Cancer Progression in Mouse Models

Zhang, Yan; Daquinag, Alexes C.; Traktuev, Dmitry O.; Amaya-Manzanares, Felipe; Simmons, Paul J.; March, Keith L.; Pasqualini, Renata; Arap, Wadih; Kolonin, Mikhail G.

doi:10.1158/0008-5472.can-08-3444

Cited by 282 publications

(241 citation statements)

References 54 publications

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“…In animal studies, administered ASC engraft tumors, which results in accelerated cancer progression. 8,9,[25][26][27] Our findings confirmed by data from other laboratories demonstrate tumor homing of endogenous ASC in obesity, which is concomitant with increased vascularization and adipogenesis promoting survival and proliferation of neighboring malignant cells. [28][29][30][31][32] The apparent contribution of ASC to the tumor stroma has raised a question regarding the safety of lipotransfer procedures in cancer patients.…”

Section: Introductionsupporting

confidence: 88%

Cytokine signaling regulating adipose stromal cell trafficking

Zhang

Kolonin

2016

Adipocyte

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Adipocyte progenitors, known as adipose stromal cells (ASC), can become mobilized, recruited by tumors, and contribute to cancer progression. Mechanisms underlying ASC trafficking have remained obscure. We recently reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing CXCR1 in obesity. As a candidate mechanism of CXCL1 activation, we identified interleukin (IL)-22, systemic circulation of which is increased in obesity. It has been reported that IL-22 signaling through IL-22R is upstream of CXCL1. Here, we provide evidence that IL-22 expression by leukocytes infiltrating WAT and IL-22R expression by tumors is obesity-dependent. We propose that obesity-associated adipocyte death and the resulting recruitment of leukocytes triggers the IL-22 signaling cascade that induces CXCL1 secretion by cancer cells responsible for ASC trafficking to tumors. KEYWORDS adipose stromal cell; cytokine; chemokine; CXCL1; cancer; interleukin-22; receptor; obesity Epidemiology studies have indicated that progression of many cancers is associated with obesity. 1-5 Excess white adipose tissue (WAT) directly contributes to disease progression, alongside with obesity-associated lifestyle and diet. 6,7 Our studies using mouse models have shown that excess of WAT, which is overgrown in obese individuals, promotes tumor growth irrespective of diet used to induce obesity. 8,9 WAT is composed by adipocytes and vascular/stromal cells. 10,11 Adipose stromal cells (ASC) serve as the mesenchymal progenitors of adipocytes and as endothelium-supporting perivascular cells 12-14 with potent angiogenic capacity. 15 While malignant cells with ASC properties comprise an integral component of liposarcomas, tumors derived from WAT, 16 it is benign ASC that promote carcinoma progression. Along with other WAT cells, ASC secrete hormones, inflammatory cytokines, and growth factors collectively termed adipokines, many of which have pro-tumorigenic properties. 17,18 It has been discovered that, like bone marrow mesenchymal stem cells (MSC), 19 ASC can become mobilized and traffic outside WAT. [20][21][22] Because numbers of ASC increase in obesity, we had hypothesized that WAT is a contributor to the pool of tumor stromal cells. 23,24 We have identified ASC trafficking to tumors as the mechanism underlying the obesity-cancer link. In animal studies, administered ASC engraft tumors, which results in accelerated cancer progression. 8,9,[25][26][27] Our findings confirmed by data from other laboratories demonstrate tumor homing of endogenous ASC in obesity, which is concomitant with increased vascularization and adipogenesis promoting survival and proliferation of neighboring malignant cells. [28][29][30][31][32] The apparent contribution of ASC to the tumor stroma has raised a question regarding the safety of lipotransfer procedures in cancer patients. 33,34 Specific molecular mechanisms through which ASC promote cancer are being investigated, and it is becoming apparent that paracrine factors secreted by ASC within the tumor larg...

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Section: Introductionsupporting

confidence: 88%

Cytokine signaling regulating adipose stromal cell trafficking

Zhang

Kolonin

2016

Adipocyte

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“…10,27,28 But only recently have investigations focused on the role of local adipose MSCs on the progression of breast cancer. 3,29 And no study has specifically evaluated the effects of adipose MSCs on the progression of breast cancer resembling the basal-type, which arguably has the most intriguing and complex association with adiposity. Here, we generate experimental data to support the mid-late stage involvement of resident adipose MSCs in the progression of basal-type breast cancer and, in doing so, we establish a mixed xenograft model for future elucidation of molecular mechanisms contributing to this promoting effect.…”

Section: Mesenchymal Stem Cells In Mammary Adipose Tissue Stimulate Pmentioning

confidence: 99%

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Zhao

Sachs

Wang

et al. 2012

Cancer Biology & Therapy

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“…The possibility that WAT cells may be mobilized in cancer and promote its progression has been tested for the first time in our recent work [112,113] . First, we tested whether mouse WAT cells can home to tumors.…”

Section: Animal Studies Demonstrating the Role Of White Adipose Tissumentioning

confidence: 99%

“…First, we tested whether mouse WAT cells can home to tumors. To analyze the short-term homing and engraftment capability of adipose cells, WAT SVF from mice expressing the green or red fluorescent proteins [114] (GFP or RFP) were iv-injected into mice bearing several types of model tumors [112] . Mice were sacrificed at 1 d and 3 d post-injection, and tissue sections were evaluated for the presence of GFP+ cells by immunofluorescence.…”

Section: Animal Studies Demonstrating the Role Of White Adipose Tissumentioning

confidence: 99%

“…Lungs, an established site of first-passage non-specific trapping of iv-injected cells, also contained occasional (1-5 per lung section) GFP+ cells, whereas no GFP+ cells were detected in control organs, including spleen, liver, and pancreas, as well as WAT. To assess recruitment of adipose cells by To explore long-term engraftment of WAT cells, we injected 10 6 adipose SVF cells into mice bearing tumor grafts and analyzed tissues over 2 wk [112] . Over 80% of the GFP+ cells in tumors localized within the stroma, whereas the rest of the GFP+ cells appeared associated with blood vessels.…”

Section: Animal Studies Demonstrating the Role Of White Adipose Tissumentioning

confidence: 99%

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Adipose Tissue-Derived Progenitor Cells and Cancer

Tseng¹,

Kolonin²

2013

Angiogenesis in Adipose Tissue

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Recruitment of stem cells and partially differentiated progenitor cells is a process which accompanies and facilitates the progression of cancer. One of the factors complicating the clinical course of cancer is obesity, a progressively widespread medical condition resulting from overgrowth of white adipose tissue (WAT), commonly known as white fat. The mechanisms by which obesity influences cancer risk and progression are not completely understood. Cells of WAT secret soluble molecules (adipokines) that could stimulate tumor growth, although there is no consensus on which cell populations and which adipokines are important. Recent reports suggest that WAT-derived mesenchymal stem (stromal) cells, termed adipose stem cells (ASC), may represent a cell population linking obesity and cancer.Studies in animal models demonstrate that adipokines secreted by ASC can promote tumor growth by assisting in formation of new blood vessels, a process necessary for expansion of tumor mass. Importantly, migration of ASC from WAT to tumors has been demonstrated, indicating that the tumor microenvironment in cancer may be modulated by ASC-derived trophic factors in a paracrine rather than in an endocrine manner. Here, we review possible positive and adverse implications of progenitor cell recruitment into the diseased sites with a particular emphasis on the role in cancer progression of progenitors that are expanded in obesity.

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White Adipose Tissue Cells Are Recruited by Experimental Tumors and Promote Cancer Progression in Mouse Models

Cited by 282 publications

References 54 publications

Cytokine signaling regulating adipose stromal cell trafficking

Cytokine signaling regulating adipose stromal cell trafficking

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Adipose Tissue-Derived Progenitor Cells and Cancer

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