Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study

Luan, Yi; Zhang, Yaqi; Yu, Seok-Yeong; You, Mikyoung; Xu, Pauline; Chung, Soonkyu; Kurita, Takeshi; Zhu, Jie; Kim, So-Youn

doi:10.1002/jcsm.12864

Cited by 22 publications

(14 citation statements)

References 44 publications

(97 reference statements)

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“…Gdf9-iCre mice were purchased from the Jackson Laboratory. Mice carrying a floxed allele for Pik3ca * , Abl1 , or Trp63 were generated as previously described ( 10 , 11 , 19 , 58 ). All procedures involving mice were approved by the Institutional Animal Care and Use Committee at the University of Nebraska Medical Center (UNMC).…”

Section: Methodsmentioning

confidence: 99%

TAp63 determines the fate of oocytes against DNA damage

Luan

Abazarikia

et al. 2022

Sci. Adv.

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Cyclophosphamide and doxorubicin lead to premature ovarian insufficiency as an off-target effect. However, their oocyte death pathway has been debated. Here, we clarified the precise mechanism of ovarian depletion induced by cyclophosphamide and doxorubicin. Dormant oocytes instead of activated oocytes with high PI3K activity were more sensitive to cyclophosphamide. Checkpoint kinase 2 (CHK2) inhibitor rather than GNF2 protected oocytes from cyclophosphamide and doxorubicin, as cyclophosphamide up-regulated p-CHK2 and depleted primordial follicles in Abl1 knockout mice. Contrary to previous reports, TAp63 is pivotal in cyclophosphamide and doxorubicin-induced oocyte death. Oocyte-specific Trp63 knockout mice prevented primordial follicle loss and maintained reproductive function from cyclophosphamide and doxorubicin, indicated by undetectable levels of BAX and cPARP. Here, we demonstrated that TAp63 is fundamental in determining the signaling of oocyte death against DNA damage. This study establishes the role of TAp63 as a target molecule of adjuvant therapies to protect the ovarian reserve from different classes of chemotherapy.

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Section: Methodsmentioning

confidence: 99%

TAp63 determines the fate of oocytes against DNA damage

Luan

Abazarikia

et al. 2022

Sci. Adv.

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“…360 Furthermore, dynamic wasting of BAT can be captured by a dedicated high-Fifield (7 Tesla) Bruker 7T ClinScan MRI combined with an infrared camera in the ovarian tumor mouse model. 361 Unfortunately, the information about MRI identifying thermogenic fat in clinical patients with malignancy is little.…”

Section: The Developmental Origin and Anatomical Location Of Thermoge...mentioning

confidence: 99%

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Yin

Chen

Ruze

et al. 2022

Sig Transduct Target Ther

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The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.

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“…When tumors are developing, cytokines, hormones, neuropeptides/neurotransmitters and tumor-derived factors can play a role in alliterating the metabolism of the adipose tissue throughout the body, such as inducing mitogen-activated protein kinases and the mitogen-activated protein kinase cascade reaction, thereby activating the p38 MAPK pathway [ 43 , 44 ]. Luan Y et al reported that mice with CAC showed significant activation of the p38 MAPK pathway and increased thermogenesis in the adipose tissue with high UCP1 expression [ 45 ]. It was also reported that lipolysis induced by pancreatic cancer exosomes could be attenuated in the presence of the p38 MAPK inhibitor (SB203580) in 3T3-L1 and human adipocytes [ 46 ], suggesting that p38 MAPK inhibitors help slow the lipolysis of fat.…”

Section: Discussionmentioning

confidence: 99%

Reducing White Adipose Tissue Browning Using p38α MAPK Inhibitors Ameliorates Cancer-Associated Cachexia as Assessed by Magnetic Resonance Imaging

et al. 2022

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Background: Up to 80% of pancreatic cancer patients suffer from cachexia. White adipose tissue (WAT) browning caused by the tumorigenicity and progression aggravates the cancer-associated cachexia (CAC). Cancer-initiated changes in the protein-38 mitogen-activated protein kinases (p38 MAPK) pathway are likely involved in the development of CAC. Methods: p38 MAPK inhibitors, VCP979 or SB203580, were used in the in vitro and in vivo models of pancreatic cancer cachexia. Expression of uncoupling protein 1 (UCP1) in the p38 MARK pathway and the properties and level of white adipocytes were analyzed and correlated to browning, followed by immunohistochemistry and Western blotting validations. Changes in the volume and fat fraction of WAT in animals were monitored by magnetic resonance imaging (MRI). Results: The size of white adipocytes was increased after being treated with the p38 MAPK inhibitors, along with increase in the MRI-measured volume and fat fraction of WAT. Comparing two p38 MAPK inhibitors, the p38α subunit-specific inhibitor VCP979 had a better therapeutic effect than SB203580, which targets both p38α and β subunits. Conclusions: Blockade of p38 MAPK reduced the WAT browning that contributes to CAC. Thus, p38 MARK inhibitors can potentially be used as a therapy for treating CAC. Non-invasive MRI can also be applied to assess the progression and treatment responses of CAC.

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Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study

Cited by 22 publications

References 44 publications

TAp63 determines the fate of oocytes against DNA damage

TAp63 determines the fate of oocytes against DNA damage

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Reducing White Adipose Tissue Browning Using p38α MAPK Inhibitors Ameliorates Cancer-Associated Cachexia as Assessed by Magnetic Resonance Imaging

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