Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Derived miR-200c Regulates Wingless-Related Integration Site (Wnt)/β-Catenin Signaling in Prostate Cancer by Targeting Cortactin (CTTN)

Bone marrow-derived mesenchymal stem cells (BMSCs) are an integral part of cancer microenvironment. We intend to clarify BMSC-derived exosomes’ role in prostate cancer. The exosomes miR-200c secreted by BMSCs were identified by electron microscopy. The mice tumor model was used to explore the role of miR-200c’s in tumor mice. Cell invasion was assessed by transwell assay and Wnt/β-catenin expression was measured by western blot. Exosomes miR-200c derived from BMSCs promoted tumor cell invasion and activated Wnt/β-catenin signaling. miR-200c targets CTTN-mediated cell signal transduction, and blocking CTTN expression can suppression miR-200c-mediated Wnt/β-catenin signal transduction and inhibit cell invasion. In conclusion, miR-200c regulates CTTN, thereby inducing Wnt/β-catenin signaling to enhance tumor growth.

Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment

Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.

Withholding of M-CSF Supplement Reprograms Macrophages to M2-Like via Endogenous CSF-1 Activation

Macrophage colony-stimulating factor (M-CSF or CSF-1) is known to have a broad range of actions on myeloid cells maturation, including the regulation of macrophage differentiation, proliferation and survival. Macrophages generated by M-CSF stimulus have been proposed to be alternatively activated or M2 phenotype. M-CSF is commonly overexpressed by tumors and is also known to enhance tumor growth and aggressiveness via stimulating pro-tumor activities of tumor-associated macrophages (TAMs). Currently, inhibition of CSF-1/CSF-1R interaction by therapeutic antibody to deplete TAMs and their pro-tumor functions is becoming a prevalent strategy in cancer therapy. However, its antitumor activity shows a limited single-agent effect. Therefore, macrophages in response to M-CSF interruption are pending for further investigation. To achieve this study, bone marrow derived macrophages were generated in vitro by M-CSF stimulation for 7 days and then continuously grown until day 21 in M-CSF absence. A selective pressure for cell survival was initiated after withdrawal of M-CSF. The surviving cells were more prone to M2-like phenotype, even after receiving interleukin-4 (IL-4) stimulation. The transcriptome analysis unveiled that endogenous CSF-1 level was dramatically up-regulated and numerous genes downstream to CSF-1 covering tumor necrosis factor (TNF), ras-related protein 1 (Rap1) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway were significantly modulated, especially for proliferation, migration and adhesion. Moreover, the phenomenal increase of miR-21-5p and genes related to pro-tumor activity were observed in parallel. In summary, withholding of CSF-1/CSF-1R interaction would rather augment than suspend the M-CSF-driven pro-tumor activities of M2 macrophages in a long run.

A Novel Bispecific Antibody Targeting EGFR and VEGFR2 Is Effective against Triple Negative Breast Cancer via Multiple Mechanisms of Action

Both EGFR and VEGFR2 frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediates angiogenesis on endothelial cells in a paracrine fashion, as well as promotes cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a BsAb co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), using publicly available sequences in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb inhibits ligand-induced activation of VEGFR2 and blocks paracrine pathway mediated by VEGF secreted from TNBC cells in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and warrants further investigation as a targeted antibody therapeutic for the treatment of TNBC.

Macrophage Responses to Environmental Stimuli During Homeostasis and Disease

Work over the last 40 years have described macrophages as a heterogeneous population that serve as the frontline surveyors of tissue immunity. As a class, macrophages are found in almost every tissue in the body and as distinct populations within discrete microenvironments in any given tissue. During homeostasis, macrophages protect these tissues by clearing invading foreign bodies and/or mounting immune responses. In addition to varying identities regulated by transcriptional programs shaped by their respective environments, macrophage metabolism serves as an additional regulator to temper responses to extracellular stimuli. The area of research known as “immunometabolism” has been established within the last decade, owing to an increase in studies focusing on the crosstalk between altered metabolism and the regulation of cellular immune processes. From this research, macrophages have emerged as a prime focus of immunometabolic studies, although macrophage metabolism and their immune responses have been studied for centuries. During disease, the metabolic profile of the tissue and/or systemic regulators such as endocrine factors, become increasingly dysregulated. Owing to these changes, macrophage responses can become skewed to promote further pathophysiologic changes. For instance, during diabetes, obesity and atherosclerosis, macrophages favor a pro-inflammatory phenotype; whereas in the tumor microenvironment, macrophages elicit an anti-inflammatory response to enhance tumor growth. Herein we have described how macrophages respond to extracellular cues including inflammatory stimuli, nutrient availability and endocrine factors that occur during and to further promote disease progression.

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity–metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor–adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.