**7. Conclusion**

Obesity can contribute to cancer progression through a variety of mechanisms. However, the main effects of obesity in the context of cancer are activation of pathways that lead to drug resistance, inflammation, and dysregulation of sex hormones and adipokines. The adipokine leptin plays a central role in the contribution of obesity to cancer progression, as it is over-expressed in obesity and contributes to insulin secretion and inflammation. Estrogen, IGF-1, and inflammatory factors also play pivotal roles cancer progression in the context obesity. However, the mechanisms discussed in this chapter are by no means an exhaustive list of what is known, and more research must still be done to completely understand the interplay between adipose tissue and the tumor microenvironment.

**49**

**Author details**

provided the original work is properly cited.

Nicole Bonan and Katie DeCicco-Skinner\*

\*Address all correspondence to: decicco@american.edu

*Obesity as a Promoter of Cancer Development and Progression*

*DOI: http://dx.doi.org/10.5772/intechopen.80516*

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Biology, American University, Washington, DC, United States

*Obesity as a Promoter of Cancer Development and Progression DOI: http://dx.doi.org/10.5772/intechopen.80516*

*Obesity*

and inflammation [46].

**7. Conclusion**

during glycolysis in cancer cells [46].

The TME can also induce hypoxia via anaerobic respiration, even in the presence of oxygen [46]. Under hypoxic conditions, ASCs are recruited to the tissue and are stimulated to secrete VEGF. This allows formation of blood vessels and angiogenesis [17]. Adipocytes can also contribute to angiogenesis in the TME. Adipocytes in obese patients have a higher expression of HIF-1α, which is largely because the adipocytes are rapidly expanding and proliferating in response to nutrient excess. This HIF-1α simulates VEGF secretion. Hypoxia in the adipose tissue also induces

HIF-1α is a transcription factor that activates hypoxia response elements. In normal conditions, it is hydrolyzed by prolyl hydroxylase domain proteins (PHDs) and ubiquitinated by Von Hippel-Lindau (VHL), which prevents the transcription factor from activating its targets. In hypoxia, however, PHDs and VHL are inhibited. HIF-1α can then bind and activate genes that induce macrophage infiltration

HIF-1α can also regulate expression of glycolytic enzymes. This effect is especially important during the metabolic reprogramming that occurs as a result of the Warburg Effect. Most notably, lactate dehydrogenase alpha (LDHα) is transactivated exclusively by HIF-1α. LDHα is responsible for converting pyruvate to lactate

OXPHOS. One of the genes that HIF-1α activates is miR-210, a type of miRNA that is overexpressed in hypoxia in many cancer cells. miRNAs are small stretches of RNA that can bind an inhibit expression of target genes. As such, miR-210 is used as a biomarker for tumor hypoxia and is generally correlated with a worse prognosis. miRNAs bind mRNA to block their transcription, and miR-201 binds mRNAs that are needed for mitochondrial activity. miR-210 can also stabilize HIF-1α, which allows the transcription factor to bind and activate hypoxia-inducing genes. In this

Obesity can contribute to cancer progression through a variety of mechanisms. However, the main effects of obesity in the context of cancer are activation of pathways that lead to drug resistance, inflammation, and dysregulation of sex hormones and adipokines. The adipokine leptin plays a central role in the contribution of obesity to cancer progression, as it is over-expressed in obesity and contributes to insulin secretion and inflammation. Estrogen, IGF-1, and inflammatory factors also play pivotal roles cancer progression in the context obesity. However, the mechanisms discussed in this chapter are by no means an exhaustive list of what is known,

and more research must still be done to completely understand the interplay

In addition to activating glycolytic pathways, HIF-1α can also block

IL-6 secretion, which can promote insulin secretion [46].

way, miR-210 can also contribute to increase hypoxia [46].

between adipose tissue and the tumor microenvironment.

**48**
