*4.3. Inflammation*

Inflammations have been shown to promote the development and progression of prostate cancer [85]. A HFD with consequent obesity causes adipose tissue inflammation and cytokine secretion [86]. Accordingly, Liu et al. demonstrated that Pten +/- mice receiving a high-calorie diet exhibited neoplastic progression with stromal infiltration of inflammatory cells, such as macrophages, T cells, and inflammatory monocytes, into the prostates [40]. Additionally, the increased inflammatory response to a high-calorie diet was supported by the elevation in the expression of CD3, CD45, FoxP3, MCP-1, IL-6, and TNF alpha. Microarray analysis using TRAMP mice models showed that HFD feeding increased serum levels of MCP-1, MCP-5, TIMP-1, IL-16, CCL12, CXCL1, CXCL10, and CXCL13 [41]. Similar results were observed in the sera of TRAMP-C2 allograft models. Zhang et al. demonstrated that adipose stromal cell recruitment to tumors of RM1 mouse prostate cancer xenografts via CXCL1 and CXCL8 chemokines promoted prostate cancer progression [49]. Another study showed that MycCaP xenografted immunocompetent FVB mice receiving a diet rich in omega-3 exhibited tumor suppression, as well as lower gene expression of markers for M1 and M2 macrophages, associated cytokines (IL-6, TNF alpha, and IL-10), and the chemokine CCL-2. Hayashi et al. showed that a HFD increased the prostate weight and percentage of Ki67-positive MDSCs, as well as the M2/M1 macrophage ratio, in HFD-fed model mice with a higher serum IL-6 levels [54]. Furthermore, celecoxib suppressed tumor growth in HFD-fed but not CD-fed model mice, which suggested that HFD-induced tumor growth was associated with local inflammation. Taken together, tumor-infiltrating macrophages may perhaps be a key factor in HFD-induced prostate cancer progression [54]. One of our previous studies had demonstrated that the MCP-1/CCR2 pathway, a key regulator of macrophage infiltration, was highly associated with HFD-induced LNCaP xenograft tumor growth, supporting the results presented herein [33]. We also found that the expression of macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor beta, was stimulated by palmitic acid in vitro, while mice receiving a HFD containing high amounts of palmitic acid had LNCaP had significantly greater xenograft tumor growth, serum MIC1 levels, and fatty acid levels in xenograft tumors than those receiving an LFD in vivo [37]. Such lines of evidence suggesting the association between cytokines and tumor–macrophage interaction support the notion that tumor-associated macrophages play a role in HFD-induced prostate cancer development and progression. Another mouse xenograft experiment concluded that HFD enhanced prostate cancer metastasis and invasiveness through FABP4 and interleukin-8 upregulation [53]. FABP4, an abundant protein in adipocytes that is influenced by a HFD or obesity, may enhance prostate cancer progression and invasiveness by upregulating matrix metalloproteinases and cytokine production in the prostate cancer stromal microenvironment [53]. In one study demonstrating tumor growth decline among Pten KO mice receiving omega-3 fatty acid, the group with an omega-3-enriched diet exhibited a reduction in CD3+ lymphocyte levels and tumor microvessel density [18]. These lines of evidence sugges<sup>t</sup> that a stromal microenvironment, including infiltration of immune cells, is associated with dietary-fat induced prostate cancer carcinogenesis. Moreover, other cytokines and chemokines, including TWEAK, (CCL)3, CCL4, and CCL5, had been found to be potentially associated with HFD-induced prostate cancer progression according to previous literatures [41,57,87].

The role of adipocyte function on HFD feeding was evaluated in a recent study [50]. Accordingly, Cav-1 secretion from fat tissue of HFD-fed mice was increased, while hypertrophied adipocytes were responsible for enhanced Cav-1 secretion in obese mice. Furthermore, secreted Cav-1 was taken up by the preadipocytes and LNCaP cells. The impact of hypertrophied adipocyte-induced Cav-1 secretion on prostate cancer progression and diet- and/or obesity-modulated adipose function could be associated with prostate inflammation and prostate carcinogenesis. Moreover, adipose tissues are known to enhance cancer progression via several underlying mechanisms, such as aromatization of adrenal androgens to estrogens in the adipocyte and deregulation of the expression and secretion of the adipokines [88,89]. Therefore, it is worthwhile to assess the role of quantitative and qualitative modulation of adipose tissues on prostate cancer progression using preclinical models.

In summary, the interaction among systematic and/or adipose secreted cytokines, inflammation, and immune cell infiltration into tumors may have a promising mechanistic role in HFD-induced prostate cancer development and progression.
