Chemoresistance: Intricate Interplay Between Breast Tumor Cells and Adipocytes in the Tumor Microenvironment

Mentoor, Ilze; Engelbrecht, Anna‐Mart; Jaarsveld, Paul J van; Nell, Theo

doi:10.3389/fendo.2018.00758

Cited by 37 publications

(36 citation statements)

References 213 publications

(253 reference statements)

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“…Finally, obese breast cancer patients have been shown to be more resistant to chemotherapy, the main standard of care of metastatic breast cancer. Obesity has been shown to contribute to chemoresistance by altering drug pharmacokinetics, inducing chronic inflammation, as well as altering tumor-associated adipocyte adipokine secretion 32 . The role of obesity-driven ECM production in chemoresistance remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors

Wishart

Peng

Conner

et al. 2020

Preprint

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The extracellular matrix (ECM) is a major component of the tumor microenvironment that supports cellular growth, promotes local invasion from the primary tumor, and contributes to metastatic outgrowth in sites of colonization. Obesity is a systemic disease that causes chronic inflammation which can lead to ECM deposition and ultimately fibrosis in adipose tissues such as the mammary gland. Overweight breast cancer patients have increased metastasis to the lung and liver, exhibit resistance to chemotherapy and have worse outcomes. We found that ECM isolated from the mammary gland of both tumor-bearing and obese mice increased invasion of breast cancer cells and set out to investigate whether obesity-driven changes in ECM could identify novel drivers of invasion and metastasis in breast cancer. We performed proteomics of the mammary fat pads of both lean and obese mice and identified the entire landscape of obesity-driven ECM changes. In particular, we focused on Collagen VI, an ECM protein secreted by adipocytes in mammary tissues. Collagen VI is upregulated in the ECM of obese and tumor-bearing mice and is associated with poor outcome in human breast cancer. We found that Collagen VI drives adhesion, migration and invasion of several human breast cancer cell lines via crosstalk between the adhesion receptor NG2 and the receptor tyrosine kinase EGFR, and activation of MAPK signaling. Overall, these studies demonstrate that obesity can have profound effects on the ECM composition of tissues, which in turn can promote local invasion and metastasis. these studies provide a novel mechanism by which obesity contributes to tumor progression and metastasis. Methods

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Section: Discussionmentioning

confidence: 99%

Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors

Wishart

Peng

Conner

et al. 2020

Preprint

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“…The role of FAs in cancer progression and treatment resistance implicates various physiological functions of FAs in relation to both dietary intake and de novo synthesized FAs. It is proposed to be achieved by (i) alterations in cell membrane composition, (ii) the biosynthesis of lipid-signaling molecules, and (iii) its role in metabolic reprogramming as an energy source [reviewed in (9,10)]. Both SFAs and MUFAs are implicated in alterations within cancer cell membrane composition known as membrane lipid saturation.…”

Section: Introductionmentioning

confidence: 99%

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

et al. 2020

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Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.

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“…In fact, Bcl-2 shows as well anti-autophagic activity by stabilizing lysosomal membrane and preventing lysosomal destabilization [100,101]. As a result, cancer cells, that express elevated Bcl-2 levels, are more chemoresistant to the standard treatments that activate either apoptosis or autophagic cell death [102,103]. Not surprisingly, we found that HepG2 cells upon NP treatment did not exhibit lysosomal dysfunction (Figure 5g) and destabilization (Figure 5f and Supplementary Figure S6).…”

Section: P53 Sub-cellular Localization Mediates Hepatic Cell Responsementioning

confidence: 77%

Iron Oxide Nanoparticle-Induced Autophagic Flux Is Regulated by Interplay between p53-mTOR Axis and Bcl-2 Signaling in Hepatic Cells

Uzhytchak

Smolková

Lunová

et al. 2020

Cells

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Iron oxide-based nanoparticles have been repeatedly shown to affect lysosomal-mediated signaling. Recently, nanoparticles have demonstrated an ability to modulate autophagic flux via lysosome-dependent signaling. However, the precise underlying mechanisms of such modulation as well as the impact of cellular genetic background remain enigmatic. In this study, we investigated how lysosomal-mediated signaling is affected by iron oxide nanoparticle uptake in three distinct hepatic cell lines. We found that nanoparticle-induced lysosomal dysfunction alters sub-cellular localization of pmTOR and p53 proteins. Our data indicate that alterations in the sub-cellular localization of p53 protein induced by nanoparticle greatly affect the autophagic flux. We found that cells with high levels of Bcl-2 are insensitive to autophagy initiated by nanoparticles. Altogether, our data identify lysosomes as a central hub that control nanoparticle-mediated responses in hepatic cells. Our results provide an important fundamental background for the future development of targeted nanoparticle-based therapies.

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Chemoresistance: Intricate Interplay Between Breast Tumor Cells and Adipocytes in the Tumor Microenvironment

Cited by 37 publications

References 213 publications

Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors

Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

Iron Oxide Nanoparticle-Induced Autophagic Flux Is Regulated by Interplay between p53-mTOR Axis and Bcl-2 Signaling in Hepatic Cells

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