The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment.

The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment.

The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.

Autologous CXCR4+ Hematopoietic Stem Cells Injected into the Scar Tissue of Chronic Myocardial Infarction Patients Normalizes Tissue Contractility and Perfusion.

BACKGROUND: Chronic myocardial infarction (CMI), represents a public health and a financial burden. Since stem cell transplant is used to regenerate cardiac tissue after acute myocardial infarction. AIM OF THE STUDY: To determine if autologous CXCR4 stem cells could restore damaged myocardial tissue in patients with CMI lesions. METHODS: 20 NYHA grade III male patients with CMI defined by clinical, biochemical, ECG and echocardiographic parameters were included. Patients were treated with G-CSF for 6 d before isolating their autologous stem cells from PBMCs. Cell phenotyping was done by cytofluorometry using monoclonal antibodies (anti-CXCR4, -CD34, -48, -117, -133, -Ki67, -SDF1 and CXCR4); CXCR4 cell subpopulations isolated by sorting were adjusted to 1 × 108 cells by subpopulation and injected in a circular pattern into the cicatrix previously defined by echocardiography. RESULTS: Patients were followed for 6 and 12 months. Six months after cell implant improvements in left ventricle ejection fraction (from 33-50%), stress rate values (from -3/-9% to -18/-22%), stress tests (from 4-12 METS), and the quantity of left ventricle affected segments (3-9) disappeared according to the G-SPECT images. 12 months evaluations did not show significant differences. Interestingly, 3 months after cell implant the ECG showed normal electrical activity in 9 patients whereas after 6 months it was normal in all the patients. CONCLUSIONS: These results ratify that locally injected autologous CXCR4+ bone marrow-derived stem cells have a physiological and a clinical impact in patients with CMI.