Obesity and Cancer: An Angiogenic and Inflammatory Link - PubMed (original) (raw)

Review

Dai Fukumura et al. Microcirculation. 2016 Apr.

Abstract

With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.

Keywords: IL-1β; IL-6; VEGFR-1; cytokines; desmoplasia; hypoxia; immune environment; metformin; obesity.

© 2016 John Wiley & Sons Ltd.

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Figures

Figure 1

Figure 1

Angiogenesis and vessel remodeling during adipogenesis in the mouse dorsal skinfold chamber after 3T3-F442A cell implantation. (A, B) Macroscopic images 9 days after implantation. (C, D) Multiphoton laser-scanning microscopy images 28 days after preadipocyte implantation. Images were obtained by maximum intensity projection of 31 optical slices, each 5 _μ_m thick: the top 150-_μ_m de novo adipose tissue layer (C) and the bottom 150-_μ_m host subcutaneous layer (D). (E through H) High-power microscopic images of fluorescence contrast-enhanced blood vessels at 7 days (E), 14 days (F), 21 days (G), and 28 days (H) after implantation. Bars indicate 5 mm (A), 0.5 mm (B), 200 _μ_m (C, D), and 100 _μ_m (E through H), respectively. This figure is reproduced from Fukumura et al., Circ Res, 2003, with permission of the publisher.

Figure 2

Figure 2

Effect of VEGFR2 blockade on angiogenesis and adipogenesis. (A, B) Visualization of rhodamine–dextran contrast-enhanced blood vessels 21 days after preadipocyte implantation with control rat IgG (A) and DC101, rat monoclonal anti-mouse VEGFR2 antibody (B) treatments. (C through F) Quantitative analyzes of tissue neovascularization; C, number of vessel segments; D, vascular length density; E, vessel diameter; F, vessel volume. Filled circles represent control IgG treatment (n = 6 mice); open squares, DC101 treatment (n = 6 mice). *P<0.01 as compared with IgG by two-tailed _t_-test. This figure is reproduced from Fukumura et al., Circ Res, 2003, with permission from the publisher.

Figure 3

Figure 3

Effects of VEGFR1 (MF1) and VEGFR2 (DC101) blockade in mice with DIO. (A) Body weight gain relative to weight at day 0 for mice given different diets and treatments. Male C57BL6 mice, 10–12 weeks old at time 0, were used for all groups. All diets and treatments began at day 0, at dosages and schedules as described in the Methods section. DC101 + HFD, DC101 treatment, white triangles (n = 5). MF1 + HFD, MF1 treatment, black squares (n = 5). HFD controls, no treatment (n = 4) or PBS treatment (n = 4), white circles. LFD: standard diet controls, crosses (n = 4). All data reported as mean ± SEM. Asterisks denote significant difference between DC101 + HFD and HFD groups (p, 0.05). This figure is reproduced from Tam et al., PLOS one, 2009, with permission from the publisher.

Figure 4

Figure 4

(A) Metformin treatment associates with reduced hyaluronan levels in human pancreatic cancers in overweight/obese patients. (i) Representative histology images showing the effect of metformin on tumor hyaluronan levels in normal weight or overweight/obese patients (n = 22 controls, 7 metformin). (ii) Immunohistochemical analysis of total tumor hyaluronan levels. Metformin decreases the hyaluronan-positive area fraction (%) in patients with BMI >25. Data are presented as the mean ± standard error. *p < 0.05 vs. control in patients with BMI >25. (B) Metformin reduces hyaluronan production by PSC. (i) PSCs were incubated in vitro with metformin (1 mM) for 48 hours. Representative immunocytochemistry images showing the effect of metformin on tumor hyaluronan and COL-I levels in human PSCs in vitro (n = 2). (ii) Quantification of hyaluronan expression in PSCs. Metformin decreases the expression of hyaluronan on PSCs. _α_SMA denotes activated PSCs. (C) Metformin inactivates PSCs and TAMs, alleviates the fibroinflammatory tumor microenvironment and reduces metastasis. Metformin treatment reduces COL-I and HA production by PSCs, leading to decreased fibrosis in PDACs. Metformin treatment also reduces cytokine production, infiltration, and M2 polarization of TAMs, leading to decreased inflammation. These lead to improved desmoplasia and reduced ECM remodeling, EMT, and metastasis. This figure is reproduced from Incio et al., PLOS One, 2015, with permission from the publisher.

Figure 5

Figure 5

The evolution of the mouse tumor model. For preclinical cancer study, we have observed an evolution of mouse models to better represent the clinical setting: It evolves from a heterotopic to an orthotopic xenograft, from xenograft tumors in immunodeficient mice to syngeneic models, from transplantation model to genetic mouse models that better reflect the initial stages of tumor development or patient-derived xenografts to accurately represent tumor heterogeneity. Finally, we need to incorporate the obese mouse model as another dimension of improvement of the mouse model to better mimic patient population.

Figure 6

Figure 6

Obesity-tailored rethinking the approach to pre-clinical cancer research in light of the current obesity epidemics. Obesity patients may respond differently to a treatment or need additional therapy in order to make the treatment effective. The development of such strategy requires the use of animal models that better mimic biology and microenvironment of obese patients.

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References

    1. Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 2008;15:833–839. - PubMed
    1. Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, Munoz M, Quijano Y, Cubillo A, Rodriguez-Pascual J, Plaza C, de Vicente E, Prados S, Tabernero S, Barbacid M, Lopez-Rios F, Hidalgo M. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer. 2013;109:926–933. - PMC - PubMed
    1. Anisimov VN. Metformin for prevention and treatment of colon cancer: a reappraisal of experimental and clinical data. Curr Drug Targets. 2016;17:439–446. - PubMed
    1. Anisimov VN, Bartke A. The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol. 2013;87:201–223. - PMC - PubMed
    1. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. 1999. Biochem Biophys Res Commun. 2012;425:560–564. - PubMed

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