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Journal ArticleDOI: 10.1016/J.CMET.2021.01.018

Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.

02 Mar 2021-Cell Metabolism (Elsevier BV)-Vol. 33, Iss: 3
Abstract: Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment (TME), we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes attenuated obesity-driven tumor growth. Similarly, genetic inhibition of creatine import into cancer cells reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals upregulated the fatty acyl-CoA synthetase Acsbg1 to promote creatine-dependent tumor progression. These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the TME necessary for obesity-driven breast cancer progression.

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Topics: Tumor progression (62%), Breast cancer (58%), Cancer cell (57%) ... show more

10 results found

Open accessJournal ArticleDOI: 10.3390/NU13051633
Bo Li1, Lili YangInstitutions (1)
13 May 2021-Nutrients
Abstract: Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.

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Topics: Creatine (61%), Cancer immunotherapy (51%)

4 Citations

Journal ArticleDOI: 10.1016/J.CMET.2021.02.011
Marc L. Reitman1Institutions (1)
02 Mar 2021-Cell Metabolism
Abstract: Obesity is a risk factor for many cancers. Maguire et al. (2021) found increased creatine synthesis by the adipocytes adjacent to breast cancers in obese mice. The creatine is transported into the cancer cells, producing larger tumors, possibly due to greater energy availability.

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Topics: Breast cancer (56%), Creatine (52%)

1 Citations

Journal ArticleDOI: 10.1016/J.CMET.2021.08.012
Gang Wei1, Honglin Sun1, Kai Dong, Libing Hu2  +16 moreInstitutions (6)
05 Oct 2021-Cell Metabolism
Abstract: Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.

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1 Citations

Open accessJournal ArticleDOI: 10.3390/CANCERS13133327
02 Jul 2021-Cancers
Abstract: Disruption of metabolic homeostasis at the organismal level can cause metabolic syndrome associated with obesity. The role of adipose tissue in cancer has been investigated over the last several decades with many studies implicating obesity as a risk factor for the development of cancer. Adipose tissue contains a diverse array of immune cell populations that promote metabolic homeostasis through a tightly controlled balance of pro- and anti-inflammatory signals. During obesity, pro-inflammatory cell types infiltrate and expand within the adipose tissue, exacerbating metabolic dysfunction. Some studies have now shown that the intracellular metabolism of immune cells is also deregulated by the lipid-rich environment in obesity. What is not fully understood, is how this may influence cancer progression, metastasis, and anti-tumor immunity. This review seeks to highlight our current understanding of the effect of adipose tissue on immune cell function and discuss how recent results offer new insight into the role that adipose tissue plays in cancer progression and anti-tumor immunity.

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Topics: Adipose tissue (64%), Adipocyte (54%), Cancer (50%)


35 results found

Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.02.013
Douglas Hanahan1, Robert A. Weinberg2Institutions (2)
04 Mar 2011-Cell
Abstract: The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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42,275 Citations

Journal ArticleDOI: 10.1056/NEJMOA021423
Abstract: background The influence of excess body weight on the risk of death from cancer has not been fully characterized. methods In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. results The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. conclusions Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.

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Topics: Overweight (55%), Mortality rate (55%), Population (54%) ... show more

6,611 Citations

Journal ArticleDOI: 10.1016/S0140-6736(08)60269-X
Andrew G Renehan1, Margaret Tyson1, Matthias Egger2, Matthias Egger3  +2 moreInstitutions (3)
16 Feb 2008-The Lancet
Abstract: Summary Background Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. Methods We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m 2 increase in BMI. Findings We analysed 221 datasets (141 articles), including 282 137 incident cases. In men, a 5 kg/m 2 increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1·52, p 2 increase in BMI and endometrial (1·59, p Interpretation Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.

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Topics: Body mass index (52%), Meta-analysis (51%), Cancer (51%) ... show more

4,045 Citations

Book ChapterDOI: 10.1007/978-1-4614-5647-6_1
Jiemin Ma1, Ahmedin Jemal1Institutions (1)
01 Jan 2013-
Abstract: Among U.S. women, breast cancer is the most commonly diagnosed cancer (excluding skin cancers) and the second leading cause of cancer death, following lung cancer. In 2012, an estimated 226,870 new cases of invasive breast cancer and 39,510 breast cancer deaths are expected to occur among U.S. women. Breast cancer rates vary largely by race/ethnicity and socioeconomic status (SES), and geographic region. Death rates are higher in African American women than in whites, despite their lower incidence rates. Historically, breast cancer was recognized as a disease of western countries. However, over the past 20 years, breast cancer incidence and mortality rates have been increasing rapidly in economically less developed regions. According to 2008 GLOBOCAN estimates, half of the new worldwide breast cancer cases (1.38 million) and 60 % of the breast cancer deaths (458,000) occurred in developing countries. This chapter reviews breast cancer incidence and mortality patterns among women in the U.S. and worldwide, and the possible explanations for these patterns.

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Topics: Breast cancer (73%), Cancer (65%), Mortality rate (54%)

2,748 Citations

Open accessJournal ArticleDOI: 10.1007/S10549-009-0674-9
Abstract: Validating prognostic or predictive candidate genes in appropriately powered breast cancer cohorts are of utmost interest. Our aim was to develop an online tool to draw survival plots, which can be used to assess the relevance of the expression levels of various genes on the clinical outcome both in untreated and treated breast cancer patients. A background database was established using gene expression data and survival information of 1,809 patients downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays). The median relapse free survival is 6.43 years, 968/1,231 patients are estrogen-receptor (ER) positive, and 190/1,369 are lymph-node positive. After quality control and normalization only probes present on both Affymetrix platforms were retained (n = 22,277). In order to analyze the prognostic value of a particular gene, the cohorts are divided into two groups according to the median (or upper/lower quartile) expression of the gene. The two groups can be compared in terms of relapse free survival, overall survival, and distant metastasis free survival. A survival curve is displayed, and the hazard ratio with 95% confidence intervals and logrank P value are calculated and displayed. Additionally, three subgroups of patients can be assessed: systematically untreated patients, endocrine-treated ER positive patients, and patients with a distribution of clinical characteristics representative of those seen in general clinical practice in the US. Web address: . We used this integrative data analysis tool to confirm the prognostic power of the proliferation-related genes TOP2A and TOP2B, MKI67, CCND2, CCND3, CCNDE2, as well as CDKN1A, and TK2. We also validated the capability of microarrays to determine estrogen receptor status in 1,231 patients. The tool is highly valuable for the preliminary assessment of biomarkers, especially for research groups with limited bioinformatic resources.

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Topics: Survival analysis (56%), Hazard ratio (53%), Breast cancer (53%) ... show more

2,024 Citations