To our knowledge, these are the first results showing PTEN loss in CAFs in CRC patients. Although more research is required, we expect that it might be a prognostic factor in CRC patients. In our large cohort of advanced CRC patients with synchronous and metachronous distant metastasis, we demonstrated the regional heterogeneity of stromal microenvironment factors according to the tumor location. The amount of microvasculature measured by LVD and MVD was also heterogeneous in relation to the metastatic organ examined. By Cox regression analysis, center LVD and MVD, periphery LVD, and CAFs in distant metastasis were independently associated with patients’ prognosis in addition to synchronous distant metastasis, age, and perineural invasion. Heterogeneity of microenvironment, not only of cancer cells, is suggested to contribute to tumor heterogeneity and biologic complexity, thus it should be considered in managing CRC patients. In addition, our results showed that PTEN expression was altered in CAFs of CRCs, suggesting that CAFs might have altered gene expression and play an active role in cancer progression. To implement effective treatment and prevention strategies, the major risk factors of CAD need to be identified. In addition, these risk factors can explain only a subgroup of CAD patients, which suggests that more risk factors need to be identified to explain the remaining patients. However, there are many endogenous protective factors against vascular injury and left ventricular remodeling, such as endothelial nitric oxide synthase, atrial natriuretic peptide and tissue kallikrein-kinin/bradykinin system. Their association with CAD patients remains to be elucidated. The LY2835219 kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins. This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins, which liberate kinins from low – and high molecular weight kininogen. The tissue kallikreins are serine proteases encoded by highly conserved multigene families. Tissue kallikrein, encoded by gene KLK1, cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which have been shown to reduce elevated blood pressure and protect the heart in human and animal models. Using transgenic and somatic gene transfer approaches to achieve a continuous supply of kallikrein–kinin in vivo, the tissue kallikrein–kinin system exhibits protective effects in hypertension, associated insulin resistance in type 2 diabetes, cardiovascular, renal and central nervous systems via suppression of oxidative stress. Our previous study demonstrated that overexpression of TK attenuated type 2 diabetes-induced hypertension and renal damage. More recently, it was found that the pleiotropic effects of TK include inhibition of apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promotion of angiogenesis and neurogenesis in different experimental animal models.