Recent advances in targeted therapy and immunotherapy have once again raised the hope that a cure might be within reach for many cancer types. Yet, most late-stage cancers are either insensitive to the therapies to begin with or develop resistance later. Therapy with live tumour-targeting bacteria provides a unique option to meet these challenges. Compared with most other therapeutics, the effectiveness of tumour-targeting bacteria is not directly affected by the 'genetic makeup' of a tumour. Bacteria initiate their direct antitumour effects from deep within the tumour, followed by innate and adaptive antitumour immune responses. As microscopic 'robotic factories', bacterial vectors can be reprogrammed following simple genetic rules or sophisticated synthetic bioengineering principles to produce and deliver anticancer agents on the basis of clinical needs. Therapeutic approaches using live tumour-targeting bacteria can either be applied as a monotherapy or complement other anticancer therapies to achieve better clinical outcomes. In this Review, we summarize the potential benefits and challenges of this approach. We discuss how live bacteria selectively induce tumour regression and provide examples to illustrate different ways to engineer bacteria for improved safety and efficacy. Finally, we share our experience and insights on oncology clinical trials with tumour-targeting bacteria, including a discussion of the regulatory issues.

Tumour-targeting bacteria engineered to fight cancer

In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease. Adipocytes respond to environmental cues, such as metabolic stress, by releasing endocrine factors that modulate diverse physiological processes. This Review discusses the metabolic functions of adipose tissue-derived endocrine hormones and highlights how these factors might contribute to cardiometabolic diseases.

The endocrine function of adipose tissues in health and cardiometabolic disease

It is well-established that the nutritional deficiency or inadequacy can impair immune functions. Growing evidence suggests that for certain nutrients increased intake above currently recommended levels may help optimize immune functions including improving defense function and thus resistance to infection, while maintaining tolerance. This review will examine the data representing the research on prominent intervention agents n-3 polyunsaturated fatty acids (PUFA), micronutrients (zinc, vitamins D and E), and functional foods including probiotics and tea components for their immunological effects, working mechanisms, and clinical relevance. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of antigen-presenting cell functions, and communication between the innate and adaptive immune systems. Both animal and human studies present promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA, and green tea catechin EGCG in autoimmune and inflammatory disorders, and vitamin D, vitamin E, zinc, and probiotics in reduction of infection. However, many studies report divergent and discrepant results/conclusions due to various factors. Chief among them, and thus call for attention, includes more standardized trial designs, better characterized populations, greater consideration for the intervention doses used, and more meaningful outcome measurements chosen.

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Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance

Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on the activation of cells from both the innate and the adaptive immune system, although the mechanisms for such regulation are diverse. First, as a constitutive part of the cellular membrane, omega-3 fatty acids can regulate cellular membrane properties, such as membrane fluidity or complex assembly in lipid rafts. In recent years, however, a new role for omega-3 fatty acids and their derivatives as signaling molecules has emerged. In this review, we describe the latest findings describing the effects of omega-3 fatty acids on different cells from the immune system and their possible molecular mechanisms.

Effects of Omega-3 Fatty Acids on Immune Cells.

The growing prevalence of metabolic syndrome (MetS) in the U.S. and even worldwide is becoming a serious health problem and economic burden. MetS has become a crucial risk factor for the development of type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD). The rising rates of CVD and diabetes, which are the two leading causes of death, simultaneously exist. To prevent the progression of MetS to diabetes and CVD, we have to understand how MetS occurs and how it progresses. Too many causative factors interact with each other, making the investigation and treatment of metabolic syndrome a very complex issue. Recently, a number of studies were conducted to investigate mechanisms and interventions of MetS, from different aspects. In this review, the proposed and demonstrated mechanisms of MetS pathogenesis are discussed and summarized. More importantly, different interventions are discussed, so that health practitioners can have a better understanding of the most recent research progress and have available references for their daily practice.

Etiology of Metabolic Syndrome and Dietary Intervention.

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the β cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D.

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ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

Adipose tissue plays an important role in regulating female fertility, owing to not only its energy stores but also the endocrine actions of secreted adipokines. As one of the adipokines, adiponectin is almost exclusively secreted from the fat, and its circulating concentration is paradoxically reduced in obesity. Although recent studies implied a purported positive role of adiponectin in ovarian functions, definitive in vivo evidence has been sorely lacking. We have consistently observed subfertility in female adiponectin null mice and therefore postulated a protective role of adiponectin in ovarian functions. Female adiponectin null mice displayed impaired fertility, reduced retrieval of oocytes, disrupted estrous cycle, elevated number of atretic follicles, and impaired late folliculogenesis. Analysis of their sera revealed a significant decrease in estradiol and FSH but an increase in LH and testosterone at proestrus. In addition, we found marked reduction of progesterone levels at diestrus, a significant decrease in LH receptor expression as well as in the number of GnRH immunoreactive neurons. Adiponectin deficiency also altered the peak concentrations of LH surge and led to lower expression of Cytochrome P450 family 11 subfamily A member 1 (P450scc), an enzyme critical for progesterone synthesis, as well as an increase in BCL2 associated X, apoptosis regulator and Insulin like growth factor binding protein 4 in atretic follicles. These physiological and molecular events were independent of insulin sensitivity. Thus, we have revealed a novel mechanism linking adiponectin and female fertility that entails regulation of reproductive hormone balance and ovarian follicle development.

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Adiponectin Deficiency Leads to Female Subfertility and Ovarian Dysfunctions in Mice.

Objective: This study evaluates the association between serum adiponectin concentrations and the risk of endometrial cancer through a comprehensive meta-analysis of currently available clinical data. Methods: PubMed, Embase, the Chinese Biomedical Literature Database and the Science Citation Index (ISI Web of Science) were searched for studies that examined the association between blood adiponectin concentrations and the risk of endometrial cancer. Data from studies that met the inclusion criteria were systematically reviewed, and pooled analyses were performed according to the guidelines of Meta-Analysis of Observational Studies in Epidemiology and PRIMSA. Results: Eight case-control studies (including 1257 endometrial cancer patients and 2008 controls) and four nested case-control studies (including 659 endometrial cancer patients and 1398 controls) were included. We found that serum adiponectin level was inversely correlated with the risk of endometrial cancer development after pooling the case-control studies (OR = 0.50, 95% CI: 0.39-0.60; P P=0.060), particularly in postmenopausal women without current hormone replacement therapy (OR = 0.62, 95% CI: 0.44-0.86; P = 0.004). Conclusions: Meta-analysis of currently available clinical evidence supports the association between high serum adiponectin concentration and reduced risk of endometrial cancer development, particularly in the group of postmenopausal women without current hormone replacement therapy. However, additional studies with prospective design are required to fully support this linkage.

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Adiponectin and Endometrial Cancer: A Systematic Review and Meta-Analysis.

Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis among all malignancies and is resistant to almost all current therapies. Attenuated Salmonella typhimurium strain VNP20009 has been deployed as powerful anticancer agent in a variety of animal cancer models, and previous phase 1 clinical trials have proven its safety profiles. However, thus far, little is known about its effect on PDAC. Here, we established CFPAC-1 cell lines expressing an mKate2 protein and thus emitting far-red fluorescence in the subsequent xenograft implant. VNP20009 strain was further engineered to carry a luciferase cDNA, which catalyzes the light-emitting reaction to allow the observation of salmonella distribution and accumulation within tumor with live imaging. Using such VNP20009 strain and intratumoral delivery, we could reduce the growth of pancreatic cancer by inducing apoptosis and severe necrosis in a dosage dependent manner. Consistent with this finding, intratumoral delivery of VNP20009 also increase caspase-3 activity and the expression of Bax protein. In summary, we revealed that VNP20009 is a promising bacterial agent for the treatment of PDAC, and that we have established a dual fluorescent imaging system as a valuable tool for noninvasive live imaging of solid tumor and engineered bacterial drug.

https://tandfonline.com/doi/pdf/10.1080/15384047.2016.1177683

Suppression of pancreatic ductal adenocarcinoma growth by intratumoral delivery of attenuated Salmonella typhimurium using a dual fluorescent live tracking system

Previous studies have reported that Ω-6 and Ω-3 fatty acids have opposing effects on cancer development. Consuming high levels of long-chain Ω-3 polyunsaturated fatty acids (PUFAs) has been shown to reduce prostate cancer risk and increase chemotherapy sensitivity. The sdd17 gene encodes an Ω-3 fatty acid desaturase, which converts arachidonic acid into eicosapentaenoic acid (EPA). However, little is known regarding the function of the sdd17 gene in tumor cells in vitro. In the present study, prostate cancer cells were infected with the msdd17 gene, which allowed the endogenous production of Ω-3 PUFAs. The cells that expressed the msdd17 gene had high levels of long-chain Ω-3 PUFAs compared with the control cells. Expression of the msdd17 gene significantly inhibited prostate cancer cell proliferation. EPA exposure and msdd17 gene transfection each induced G2 cell cycle arrest and reduced E2F transcription factor 1 expression in prostate cancer cells. These results suggest that msdd17 gene transfection suppressed prostate cancer cell proliferation and induced G2 cell cycle arrest.

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Xiaoxi Li

Papers

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

Adiponectin Deficiency Leads to Female Subfertility and Ovarian Dysfunctions in Mice.

Adiponectin and Endometrial Cancer: A Systematic Review and Meta-Analysis.

Suppression of pancreatic ductal adenocarcinoma growth by intratumoral delivery of attenuated Salmonella typhimurium using a dual fluorescent live tracking system

An Ω-3 fatty acid desaturase-expressing gene attenuates prostate cancer proliferation by cell cycle regulation