Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer

A vast number of epidemiological studies suggest an important, but still controversial, role for obesity and adipose tissue mass in breast cancer risk and an association with tumor phenotype. The main conclusions from these studies raise the possibility that the adipose tissue can act as an effector organ that influences both cancer risk and tumor behavior. Here we also review heterotypic mechanisms in breast-cancer tumorigenesis; these mechanisms involve soluble secreted factors from peritumoral cells, extracellular-matrix components and interactions between stromal cells and tumor cells that create a specific and local peritumoral microenvironment. As a special focus, we discuss the increasing evidence for a role of peritumoral adipose tissue and secreted adipokines (such as adiponectin and leptin) in breast cancer; furthermore, the cellular and molecular basis of the peritumoral 'desmoplastic' tissue reaction observed in breast cancer is reviewed in detail.     

Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy

Solid tumors frequently contain large regions with low oxygen concentrations (hypoxia). The hypoxic microenvironment induces adaptive changes to tumor cell metabolism, and this alteration can further distort the local microenvironment. The net result of these tumor-specific changes is a microenvironment that inhibits many standard cytotoxic anticancer therapies and predicts for a poor clinical outcome. Pharmacologic targeting of the unique metabolism of solid tumors could alter the tumor microenvironment to provide more favorable conditions for anti-tumor therapy. Here, we describe a strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1). This acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation. Whereas decreased oxygenation could reduce the effectiveness of some traditional therapies, we show that it dramatically increases the effectiveness of a hypoxia-specific cytotoxin. This treatment strategy should provide a high degree of tumor specificity for increasing the effectiveness of hypoxic cytotoxins, as it depends on the activation of HIF1 and the presence of hypoxia, conditions that are present only in the tumor, and not the normal tissue.     

Bispecific antibody platforms for cancer immunotherapy

Over the past decades advances in bioengineering and expanded insight in tumor immunology have resulted in the emergence of novel bispecific antibody (bsAb) constructs that are capable of redirecting immune effector cells to the tumor microenvironment. (Pre-) clinical studies of various bsAb constructs have shown impressive results in terms of immune effector cell retargeting, target dependent activation and the induction of anti-tumor responses. This review summarizes recent advances in the field of bsAb-therapy and limitations that were encountered. Furthermore, we will discuss potential future developments that can be expected to take the bsAb approach successfully forward.     

Novel concepts in hepatocellular carcinoma: from molecular research to clinical practice

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, burdened by a constantly increasing frequency. Therapy is currently restricted to invasive techniques but prognosis and survival are still unsatisfactory, mainly because of HCC recurrence and metastasis diffusion. This review will focus on the problem of tumor recurrence and/or metastasis, pointing out the role of the tissue microenvironment in affecting HCC behavior; new experimental findings will also be discussed in the light of their implications in medical care. Finally, new therapeutic approaches will be considered, paying particular attention to the tissue microenvironment as a potential target. In conclusion, this review will attempt to stimulate debate on translational research into HCC biology, in the field of clinical applications.     

Targeting Bone Metastases: New Drugs for New Targets

Bone metastases development requires multistep and multicellular machinery consisting not only of processes shared with any types of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). The aim of this review is to depict the complex sequence of events from early cancer cells dissemination to the onset of clinically detectable bone lesions with particular attention to those molecular targets that have been investigated in order to find out new therapeutical approaches helpful in reducing clinical sequelae of skeletal metastases.     

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.     

Class 3 semaphorins: physiological vascular normalizing agents for anti‐cancer therapy

Findings from preclinical and clinical studies show that vascular normalization represents a novel strategy to enhance the efficacy of and overcome the acquired resistance to anti‐angiogenic therapies in cancer. Several mechanisms of tumour vessel normalization have been revealed. Amongst them, secreted class 3 semaphorins (Sema3), which regulate axon guidance and angiogenesis, have been recently identified as novel vascular normalizing agents that inhibit metastatic dissemination by restoring vascular function. Here, we discuss the different biological functions and mechanisms of action of Sema3 in the context of tumour vascular normalization, and their impact on the different cellular components of the tumour microenvironment.     

Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors

Predicting drug response in cancer patients remains a major challenge in the clinic. We have perfected an ex vivo, reproducible, rapid and personalized culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment. Response to signal transduction inhibitors in cancer is determined not only by properties of the drug target but also by mutations in other signaling molecules and the tumor microenvironment. As a proof of concept, we, therefore, focused on the PI3K/Akt signaling pathway, because it plays a prominent role in cancer and its activity is affected by epithelial–stromal interactions. Our results show that this culture model preserves tissue 3D architecture, cell viability, pathway activity, and global gene-expression profiles up to 5 days ex vivo. In addition, we show pathway modulation in tumor cells resulting from pharmacologic intervention in ex vivo culture. This technology may have a significant impact on patient selection for clinical trials and in predicting response to small-molecule inhibitor therapy.     

The role of the extracellular matrix in tissue distribution of macromolecules in normal and pathological tissues: potential therapeutic consequences

The interstitial space is a dynamic microenvironment that consists of interstitial fluid and structural molecules of the extracellular matrix, such as glycosaminoglycans (hyaluronan and proteoglycans) and collagen. Macromolecules can distribute in the interstitium only in those spaces unoccupied by structural components, a phenomenon called interstitial exclusion. The exclusion phenomenon has direct consequences for plasma volume regulation. Early studies have assigned a major role to collagen as an excluding agent that accounts for the sterical (geometrical) exclusion. More recently, it has been shown that the contribution of negatively charged glycosaminoglycans might also be significant, resulting in an additional electrostatical exclusion effect. This charge effect may be of importance for drug uptake and suggests that either the glycosaminoglycans or the net charge of macromolecular substances to be delivered may be targeted to increase the available volume and uptake of macromolecular therapeutic agents in tumor tissue. Here, we provide an overview of the structural components of the interstitium and discuss the importance the sterical and electrostatical components have on the dynamics of transcapillary fluid exchange.     

Mesenchymal Stem Cells in Cancer: Tumor-Associated Fibroblasts and Cell-Based Delivery Vehicles

Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.     

Malignant cells facilitate lung metastasis by bringing their own soil

Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil--stromal components including activated fibroblasts--from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated in heterotypic tumor-stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic cancer cells, significantly decreases the number of metastases and extends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has important conceptual and clinical implications for the colonization step in tumor progression.     

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

The survival and growth of tumor cells in a foreign environment is considered a rate-limiting step during metastasis. To identify genes that may be essential for this process, we isolated highly metastatic variants from a poorly metastatic human melanoma cell line and performed expression analyses of metastases and primary tumors from these cells. GPR56 is among the genes markedly down-regulated in the metastatic variants. We show that overexpression of GPR56 suppresses tumor growth and metastasis, whereas reduced expression of GPR56 enhances tumor progression. Levels of GPR56 do not correlate with growth rate in vitro, suggesting that GPR56 may mediate growth suppression by interaction with a component in the tumor microenvironment in vivo. We show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. We discuss the mechanisms whereby GPR56-TG2 interactions may suppress tumor growth and metastasis.     

The tumor microenvironment: part 1

For years the mutated, highly proliferating neoplastic cells were presented as the only important agent in tumors; however, during the last 3-4 decades it has become clear that the microenvironment of the cancer cells plays a determinative role in the malignant evolution of neoplasia. Cancers are in fact heterogeneous entities containing, in addition to the neoplastic cell component, cells derived of multiple lineages (fibroblasts, endothelial cells lining blood and lymphatic vessels, pericytes, adipocytes and immune system cells belonging to both innate and adaptive responses), as well as the extracellular matrix, with a large variety of soluble molecules of biological importance, constituting a complex organ-like structure. The tumor microenvironment consists in a tissue that may have a predictive significance for tumor behavior and response to therapy.     

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients.     

Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system

The field of hematopoietic oncology has traditionally focused on the study of hematopoietic cell autonomous genetic events in an effort to understand malignant transformation and develop therapeutics. Although highly rewarding in both aspects, this cell autonomous approach has failed to fully satisfy our need to understand tumor cell behavior and related clinical observations. In recent years, it has been increasingly recognized that the tumor microenvironment plays a pivotal role in cancer initiation and progression. This review will discuss recent experimental evidence in support of this view derived from investigations in both epithelial and hematopoietic systems. Based on this, conceptual views and therapeutic implications will be provided on the emerging role of the bone marrow microenvironment in leukemogenesis.     

Modulated multiparametric phosphoflow cytometry in hematological malignancies: technology and clinical applications

The advent of modulated multiparameter phosphoflow cytometry allows insight into the complexity of signal transduction networks in distinct cell subsets within a complex tissue sample. The application of this technology to hematopoietic malignancies can reveal pathogenic signaling profiles in intact tumor cells. Here, we review recent studies demonstrating the advantages and utility of this technology to inform the biological characterization of tumor cells and its applications to clinical medicine and drug development. Further, we discuss standardization and quality control approaches necessary for the adoption of this technique into clinical flow cytometry laboratories.     

Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

The Epstein–Barr virus (EBV) can cause different types of cancer in human beings when the virus infects different cell types with various latent patterns. EBV shapes a distinct and immunosuppressive tumor microenvironment (TME) to its benefit by influencing and interacting with different components in the TME. Different EBV-associated malignancies adopt similar but slightly specific immunosuppressive mechanisms by encoding different EBV products to escape both innate and adaptive immune responses. Strategies reversing the immunosuppressive TME of EBV-associated malignancies have been under evaluation in clinical practice. As the interactions among EBV, tumor cells, and TME are intricate, in this review, we mainly discuss the epidemiology of EBV, the life cycle of EBV, the cellular and molecular composition of TME, and a landscape of different EBV-associated malignancies and immunotherapy by targeting the TME.     

局部肾素血管紧张素系统与肺癌的研究进展

肺癌的发生发展是多因素造成的,治疗和预防也是多方面的.近年来,随着对肾素血管紧张素系统(RAS)逐步深入的研究,RAS得到了很大的更新,发现了许多新的组分,而且发现除了系统性的RAS外,肺癌局部组织微环境中也包含重要的RAS组分,并在肿瘤的发生发展及血管生成中发挥重要作用.本文就更新后的局部RAS与肺癌的发生发展机制作...     

Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.