Different Components Of Tumor Microenvironment Research Articles

Obesity, dysbiosis and inflammation: interactions that modulate the efficacy of immunotherapy.

Recent years have seen an outstanding growth in the understanding of connections between diet-induced obesity, dysbiosis and alterations in the tumor microenvironment. Now we appreciate that gut dysbiosis can exert important effects in distant target tissues via specific microbes and metabolites. Multiple studies have examined how diet-induced obese state is associated with gut dysbiosis and how gut microbes direct various physiological processes that help maintain obese state in a bidirectional crosstalk. Another tightly linked factor is sustained low grade inflammation in tumor microenvironment that is modulated by both obese state and dysbiosis, and influences tumor growth as well as response to immunotherapy. Our review brings together these important aspects and explores their connections. In this review, we discuss how obese state modulates various components of the breast tumor microenvironment and gut microbiota to achieve sustained low-grade inflammation. We explore the crosstalk between different components of tumor microenvironment and microbes, and how they might modulate the response to immunotherapy. Discussing studies from multiple tumor types, we delve to find common microbial characteristics that may positively or negatively influence immunotherapy efficacy in breast cancer and may guide future studies.

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin.

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

ANPEP: A Potential Regulator of Tumor Cell—Immune Metabolic Interactions in Prostate Cancer of Men of African Descent

PURPOSE Prostate cancer (PCa) is the leading cause of male cancer deaths in Africa. In USA, African American men (AA) experience higher mortality rate compared to European American men (EA). While socioeconomics factors contribute toward these disparities, distinct molecular mechanisms in AA remain important drivers. For example, in previous work, we discovered that PCa form AA men harbored a significantly higher expression of Aminopeptidase N (ANPEP) as compared with EA. Aminopeptidase N regulates immune cell function and mediates tumor cell migration but its role in PCa remains uninvestigated. METHODS We explored ANPEP expression related to a range of genomic classifiers in multiple datasets. We then prospectively examined the differentially expressed genes in PCa tissues collected from 120 AA and 120 EA patients enrolled on the VANDAAM clinical trial. We further correlated ANPEP expression with various signatures related to immune and metabolic activity. We also experimentally examined the expression of ANPEP in different components of tumor microenvironment. RESULTS In the VANDAAM study, ANPEP represents the top differentially expressed gene between AA and EA men. Our data driven approach revealed that ANPEP correlates with signature of cholesterol transport and androgen signaling. Interestingly, these signatures dominate in PCa with high macrophage infiltration. Deconvolution of immune cell content using computational approaches indeed demonstrated that only AA patients with high ANPEP expression significantly accumulated high content of inflammatory macrophages. Further experimental findings showed that ANPEP indeed represents a marker of tumor-associated macrophages, a type of immune cells known to contribute to PCa progression. CONCLUSION We have identified ANPEP as a macrophage-related gene with a potential role in cholesterol metabolism and AR signaling in AA. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry and explants derived from AA and EA PCa patients.

Exosomal miRNAs as a Promising Source of Biomarkers in Colorectal Cancer Progression.

Colorectal cancer (CRC) is the third most common type of cancer worldwide amongst males and females. CRC treatment is multidisciplinary, often including surgery, chemotherapy, and radiotherapy. Early diagnosis of CRC can lead to treatment initiation at an earlier stage. Blood biomarkers are currently used to detect CRC, but because of their low sensitivity and specificity, they are considered inadequate diagnostic tools and are used mainly for following up patients for recurrence. It is necessary to detect novel, noninvasive, specific, and sensitive biomarkers for the screening and diagnosis of CRC at earlier stages. The tumor microenvironment (TME) has an essential role in tumorigenesis; for example, extracellular vesicles (EVs) such as exosomes can play a crucial role in communication between cancer cells and different components of TME, thereby inducing tumor progression. The importance of miRNAs that are sorted into exosomes has recently attracted scientists’ attention. Some unique sequences of miRNAs are favorably packaged into exosomes, and it has been illustrated that particular miRNAs can be directed into exosomes by special mechanisms that occur inside the cells. This review illustrates and discusses the sorted and transported exosomal miRNAs in the CRC microenvironment and their impact on CRC progression as well as their potential use as biomarkers.

Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma.

Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.

Pericytes in Breast Cancer.

Breast cancer is a heterogeneous disease driven not only by evolutionally diverse cancer cell themselves but also by highly dynamic microenvironment. At the center of the tumor microenvironment, tumor vasculature plays multiple roles from supporting tumor growth to providing a route for metastasis to the distant organ sites. Blood vessels in breast cancer present with perfusion defects associated with vessel dilation, tortuosity, and poor perivascular coverage (Li et al., Ultrasound Med 32:1145-1155, 2013; Eberhard et al., Cancer Res 60:1388-1393, 2000; Cooke et al., Cancer Cell 21:66-81, 2012). Such abnormal vascular system is partly due to the morphological and molecular alteration of pericytes that is accompanied by a significant heterogeneity within the populations (Kim et al., JCI Insight 1:e90733, 2016). While pericytes are implicated for their controversial roles in breast cancer metastasis (Cooke et al., Cancer Cell 21:66-81, 2012; Gerhardt and Semb, J Mol Med (Berl) 86:135-144, 2008; Keskin et al., Cell Rep 10:1066-1081, 2015; Meng et al., Future Oncol 11:169-179, 2015; Xian et al., J Clin Invest 116:642-651, 2006), the impact of their heterogeneity on breast cancer progression, metastasis, intratumoral immunity, and response to chemotherapy are largely unknown. Due to the complexity of angiogenic programs of breast cancer, the anti-angiogenic or anti-vascular treatment has been mostly unsuccessful (Tolaney et al., Proc Natl Acad Sci U S A 112:14325-14330, 2015; Mackey et al., Cancer Treat Rev 38:673-688, 2012; Sledge, J Clin Oncol 33:133-135, 2015) and requires much in-depth knowledge on different components of tumor microenvironment and how these stromal cells are interacting and communicating to each other. Therefore, understanding pericyte heterogeneity and their differential functional contribution will shed light on new potential approaches to treat breast cancer.

Role of Distinct Natural Killer Cell Subsets in Anticancer Response.

Natural killer (NK) cells, the prototypic member of innate lymphoid cells, are important effectors of anticancer immune response. These cells can survey and control tumor initiation due to their capability to recognize and kill malignant cells and to regulate the adaptive immune response via cytokines and chemokines release. However, several studies have shown that tumor-infiltrating NK cells associated with advanced disease can have profound functional defects and display protumor activity. This evidence indicates that NK cell behavior undergoes crucial alterations during cancer progression. Moreover, a further level of complexity is due to the extensive heterogeneity and plasticity of these lymphocytes, implying that different NK cell subsets, endowed with specific phenotypic and functional features, may be involved and play distinct roles in the tumor context. Accordingly, many studies reported the enrichment of selective NK cell subsets within tumor tissue, whereas the underlying mechanisms are not fully elucidated. A malignant microenvironment can significantly impact NK cell activity, by recruiting specific subpopulations and/or influencing their developmental programming or the acquisition of a mature phenotype; in particular, neoplastic, stroma and immune cells, or tumor-derived factors take part in these processes. In this review, we will summarize and discuss the recently acquired knowledge on the possible contribution of distinct NK cell subsets in the control and/or progression of solid and hematological malignancies. Moreover, we will address emerging evidence regarding the role of different components of tumor microenvironment on shaping NK cell response.

Abstract 2395: Leptin induces an IL-6 mediated interaction between macrophages and ovarian cancer cells that prompted invasiveness and migration

Abstract Introduction: The current knowledge in ovarian epithelial carcinogenesis grants a major role for chronic inflammation in driving the multiple steps in the natural history of the most deadly gynecological cancer. Different environmental stimuli have been associated with an increased ovarian cancer risk. Growing evidence has become to support the potential role of obesity as one of the conditioning factors. Leptin, an adipokine, controlling metabolism and energy expenditure and normally circulating at higher serum levels among overweight women, has been syndicated as the pro-inflammatory mediator in obesity. So far, few are known about the role of and how leptin modulate cells to cells interactions among the different components of tumor microenvironment. Goal: In the present study we investigated the leptin effect in prompting a pro-inflammatory microenvironment, the communication between macrophages and ovarian cancer cells and the impact of this interaction in cancer cell migration and invasion. Methods: HEY ovarian cancer cell line and the THP-1 monocyte cell line were used. THP-1 cells were differentiated to macrophages by using PMA (Phorbol 12-myristate 13-acetate) 200 nM for 24h. Upon differentiation macrophages were exposed to a time course of leptin (100 ng/ml, 6h to 24h). Upon control or leptin exposure, conditioned medium was collected from macrophages (MCM), and used to measure IL-6 release to the medium and to treat HEY cell line for 24h. Secreted IL-6 was used as inflammation marker and measured by ELISA assay. Protein extracts were obtained from HEY cells upon control and MCM exposure and used to quantify epithelial mesenchymal transition (EMT) marker vimentin by Immunoblotting and Immunocytochemistry. The effects of leptin and MCM in HEY migration and invasion was assessed by Boyden chamber assay without or with matrigel, respectively. Results: Upon leptin treatment both HEY and macrophages significantly increased IL-6 release to the medium. More importantly, incubation of MCM with HEY cells resulted in a synergistic increase of IL-6 release, (from a basal release of 13,4±2 pg/mL to 2,3×104 pg/mL upon MCM exposure). Moreover, HEY cells exposure to MCM resulted in phenotypic changes that were associated to changes in vimentin expression (mainly upon exposure to 6h leptin incubated MCM). Finally, this exposure to leptin-incubated MCM significantly increased migration and invasion of HEY cells. Conclusions: Our findings support a role of leptin in prompting a pro-inflammatory microenvironment that involved an increase in IL-6 release from the macrophages. These changes induced by leptin in macrophages resulted in a cytokine secretion pattern, which consequentially modified cancer cells phenotype favoring migration and invasion and a more aggressive epithelial ovarian cancer behavior. (Funding: FONDECYT 1120292 and 3140335) Citation Format: Sumie Kato, Lorena Abarzua-Catalan, Isidora Solar-Costabal, Karen García, Jorge Branes, Gareth I. Owen, Mauricio A. Cuello. Leptin induces an IL-6 mediated interaction between macrophages and ovarian cancer cells that prompted invasiveness and migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2395. doi:10.1158/1538-7445.AM2015-2395