The shaping of new blood vessels is a significant event in cancer growth and metastasis. Therefore, the molecular system of cancer angiogenesis has garnered considerable interest in cancer research. The vascular endothelial growth factor (VEGF) and VEGF receptor pathway are recognized as the key regulators of the angiogenic process. Activation of the VEGF/VEGF-receptor pathway initiates signaling cascades that promote endothelial cell growth, migration, and differentiation. Recently, VEGF was shown to play a role in the recruitment of bone marrow-derived endothelial progenitor cells to neovascularization sites. The role of VEGF in promoting tumor angiogenesis and the occurrence of human cancers has led to the rational design and development of agents that selectively target this pathway. Moreover, these anti-VEGF/VEGF receptor agents show therapeutic potential by inhibition of angiogenesis and tumor growth in preclinical models. In this review, we summarize the role of the VEGF pathway during tumor angiogenesis.

Melatonin suppresses tumor development. However, the exact relationship between melatonin and cancer stem cells (CSCs) is poorly understood. This study found that melatonin inhibits colon CSCs by regulating the PrP -Oct4 axis. In specimens from patients with colorectal cancer, the expressions of cellular prion protein (PrP ) and Oct4 were significantly correlated with metastasis and tumor stages. Co-treatment with 5-fluorouracil (5-FU) and melatonin inhibited the stem cell markers Oct4, Nanog, Sox2, and ALDH1A1 by downregulating PrP . In this way, tumor growth, proliferation, and tumor-mediated angiogenesis were suppressed. In colorectal CSCs, PRNP overexpression protects Oct4 against inhibition by 5-FU and melatonin. In contrast, Nanog, Sox2, and ALDH1A1 have no such protection. These results indicate that PrP directly regulates Oct4, whereas it indirectly regulates Nanog, Sox2, and ALDH1A1. Taken together, our findings suggest that co-treatment with anticancer drug and melatonin is a potential therapy for colorectal cancer. Furthermore, PrP maintains cancer stemness during tumor progression. Therefore, targeting the PrP -Oct4 axis may prove instrumental in colorectal cancer therapy.

Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway.

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H2O2 to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H2O2 and associated excessive senescence. The latter was mediated by PrPC‐dependent mitochondrial functional enhancement; melatonin upregulated PrPC, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H2O2‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrPC and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs.

Mesenchymal stem cells (MSCs) are promising candidates for stem cell-based therapy in ischemic diseases. However, ischemic injury induces pathophysiological conditions, such as oxidative stress and inflammation, which diminish therapeutic efficacy of MSC-based therapy by reducing survival and functionality of transplanted MSCs. To overcome this problem, we explored the effects of melatonin on the proliferation, resistance to oxidative stress, and immunomodulatory properties of MSCs. Treatment with melatonin enhanced MSC proliferation and self-renewal via upregulation of cellular prion protein (PrP ) expression. Melatonin diminished the extent of MSC apoptosis in oxidative stress conditions by regulating the levels of apoptosis-associated proteins, such as BCL-2, BAX, PARP-1, and caspase-3, in a PrP -dependent manner. In addition, melatonin regulated the immunomodulatory effects of MSCs via the PrP -IDO axis. In a murine hind-limb ischemia model, melatonin-stimulated MSCs improved the blood flow perfusion, limb salvage, and vessel regeneration by lowering the extent of apoptosis of affected local cells and transplanted MSCs as well as by reducing infiltration of macrophages. These melatonin-mediated therapeutic effects were inhibited by silencing of PrP expression. Our findings for the first time indicate that melatonin promotes MSC functionality and enhances MSC-mediated neovascularization in ischemic tissues through the upregulation of PrP expression. In conclusion, melatonin-treated MSCs could provide a therapeutic strategy for vessel regeneration in ischemic disease, and the targeting of PrP levels may prove instrumental for MSC-based therapies.