**Section 1**

**Mechanisms of Carcinogenesis, Role of Oxidative Stress, Inflammation and DNA Damage** 

**1** 

*North Carolina,* 

*U.S.A.* 

**Targeting Tumor Microenvironments** 

*1Department of Internal Medicine, Division of Hematology/Oncology, 2Department of Anatomy and Cell Biology, Brody School of Medicine,* 

Solid tumors comprise not only cancer cells but also host stromal cells, such as vascular cells, inflammatory/immune cells, and cancer-associated fibroblasts. The crosstalk between cancer cells and stromal cells plays an important role in tumor growth, metastasis, and response to antitumor therapy (Hanahan and Weinberg, 2011; Joyce and Pollard, 2009; Petrulio et al., 2006). Cancer cells with oncogenic mutations are central to tumor formation. Endothelial cells in tumors form new blood vessels (angiogenesis) which bring oxygen and nutrients to the growing tumor (Ferrara and Kerbel, 2005), and also regulate leukocyte infiltration and tumor cell metastasis (Chouaib et al., 2010). Inflammatory cells have both tumor-promoting and tumor-preventing effects (Grivennikov et al., 2010; Hanahan and Weinberg, 2011). Fibroblasts are the most abundant cells in the tumor stroma and have been demonstrated to have tumor-promoting activities (Bhowmick et al., 2004). Moreover, cancer cells within tumors are heterogeneous and composed of distinct subpopulations with different states of tumorigenicity. One subpopulation of cells that has recently been extensively studied is the cancer initiating cell or cancer stem cell (CSC) (Cho and Clarke,

The microenvironment in solid tumors is very distinct from that in normal tissues. Due to deregulated cancer cell metabolism, highly heterogeneous vasculature and defective blood perfusion, the tumor microenvironment is characterized by hypoxia and acidosis (Cairns et al., 2006; Gatenby et al., 2006; Gatenby and Gillies, 2004). The uncontrolled proliferation of tumor cells results in a growing mass that rapidly consumes oxygen, glucose and nutrients (Gatenby and Gillies, 2004). When an oxygen diffusion limit is reached, some regions of a tumor become hypoxic. Cancer cells rely heavily upon glycolysis ('Warburg effect') to generate ATP and metabolic intermediates for biosynthesis (Gatenby and Gillies, 2004; Vander Heiden et al., 2009). There is much evidence to link the connection between the adaptation to hypoxia and the development of an aggressive tumor phenotype in both experimental and clinical settings (Chang et al., 2011; Gatenby and Gillies, 2004). In addition to hypoxia, the existence of acidosis is a defining hallmark of the tumor microenvironment.

2008), which exhibits high capacity of generating new tumors.

**1. Introduction** 

**for Cancer Prevention and Therapy** 

Li V. Yang1,2,3, Reid D. Castellone1 and Lixue Dong1

*3UNC Lineberger Comprehensive Cancer Center, Chapel Hill,* 

*East Carolina University, Greenville, North Carolina,* 
