The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

The influence of psychosocial factors on the development and progression of cancer has been a longstanding hypothesis since ancient times. In fact, epidemiological and clinical studies over the past 30 years have provided strong evidence for links between chronic stress, depression and social isolation and cancer progression. By contrast, there is only limited evidence for the role of these behavioral factors in cancer initiation. Recent cellular and molecular studies have identified specific signaling pathways that impact cancer growth and metastasis. This article provides an overview of the relationship between psychosocial factors, specifically chronic stress, and cancer progression. Keywordscancer; catecholamine; metastasis; signaling pathway; stress The major cause of death from cancer is metastasis that is resistant to conventional therapy [1]. Primary neoplasms are biologically heterogeneous and the process of metastasis consists of a series of sequential and selective steps that few cells can successfully complete. The outcome of cancer metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that are unique to a given organ micro environment [2]. Therefore, the treatment of metastasis should be targeted not only against cancer cells, but also against the host factors that contribute to and support the progressive growth and survival of metastatic cancer cells. Clinical and epidemiological studies over the last 30 years have identified psychosocial factors including stress, chronic depression and lack of social support as risk factors for cancer progression [3][4][5][6]. Whereas evidence for the role of psychosocial factors in cancer initiation is limited and some-what contradictory [7][8][9][10], support is stronger for links between psychological factors such as stress, depression and social isolation and disease progression [11,12]. Chronicity of negative affect, as manifested by depressed mood or hopelessness, appears to have stronger relationships with outcomes NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript than do stressful events, suggesting that sustained activation of negative affective pathways may provide the strongest links to cancer progression [13][14][15][16]. Moderators of stress, such as social support, have been frequently studied with respect to cancer outcomes. Social support refers to an individual's perceived satisfaction with social relationships and is thought to play a major role in buffering psychological and biological stress responses [17]. Several studies have linked high levels of social support to improved clinical outcomes in cancer patients. For example, in breast cancer patients, social support has been related to longer survival in several large-scale studies [18][19][20], although negative findings were noted in some studies [21][22][23]. Collectively, emerging evidence has shown stress and specific psychosocial factors to be associated with key elements of the metastatic cascade in both animal ...

Purpose Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth. Experimental Design Expression of dopamine receptors (DR1-DR5) was analyzed by real time reverse transcription-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis and migration were examined. For in vivo therapy, murine and human DR2-siRNA’s were incorporated into chitosan nanoparticles (CH). Results In this model of chronic stress, tumoral norepinephrine levels remained elevated while dopamine levels were significantly decreased compared to non-stressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density (MVD) as well as the stimulatory effect on apoptosis, since the DR2-antagonist eticlopride, reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cAMP levels and inhibited norepinephrine and VPF/VEGF induced Src kinase activation. Conclusions Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement.