Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.

Bone marrow mesenchymal progenitor cells (BMSC) are used for regenerating tissues of mesodermal origin, as well as tissues of different embryological derivation. Experimental evidence shows that BMSC are able to suppress the activation of the immune response by mechanisms that are still not completely understood. Thus far, in vitro studies carried using human or mouse cells indicate that autologous or allogeneic BMSC strongly suppress proliferation of T lymphocytes, triggered by cellular stimuli, nonspecific mitogenic stimuli, or antigenic peptides. Using cell proliferation and blocking assays, we demonstrated that BMSC inhibited the activation of murine splenocytes, T, and B lymphocytes. Direct contact of BMSC and target cells in a cognate fashion determined the inhibition of cell proliferation via engagement of the inhibitory molecule programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2, leading the target cells to modulate the expression of different cytokine receptors and transduction molecules for cytokine signaling. Soluble factors present on supernatants of BMSC cultures were effective in suppressing proliferation of B cells to a mitogenic stimulus. Taken together, these results highlight the complexity of the role of BMSC in regulating the immune response, asserting the possibility of their therapeutic application in transplantation and autoimmune diseases.

Objective. Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non-major histocompatibility complex-restricted manner. Use of MSCs as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. We explored the feasibility of using allogeneic MSCs as therapy for collageninduced arthritis, a mouse model for human rheumatoid arthritis.Methods. DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant, and some of the animals received an intraperitoneal injection of allogeneic MSCs.Results. A single injection of MSCs prevented the occurrence of severe, irreversible damage to bone and cartilage. MSCs induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor ␣ was significantly decreased. MSCs exerted their immunomodulatory function by educating antigen-specific Tregs.Conclusion. Our results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs. However, further studies are required before these results can be translated to clinical settings.

BackgroundColorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers.MethodsThe presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control.ResultsThe differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels.ConclusionsThese data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.

The contribution of the host's circulating progenitor cells after implantation of mesenchymal stem cells (MSC)/bioscaffold combinations for repairing bone defects has not been elucidated, although this issue affects the clinical application of the tissue engineering approach. We implanted blocks of hydroxyapatite loaded with murine MSCs into syngenic, allogenic, and immunocompromised recipients. After 8 weeks, we found that bone tissue was formed in syngenic and immunocompromised animals. The implanted cells appeared pivotal in the early stages of tissue development, but cells of the recipient's origin finally made bone. In this system, osteoprogenitors migrated from the recipient to the implant, whereas the implanted cells left the scaffold and entered the circulatory flow. We observed rapid destruction of implanted cells when allogenic MSC/bioscaffold combinations were grafted onto immunocompetent recipients without immunosuppressant therapy. This destruction blocked the recruitment process and did not allow the formation of new bone tissue. The possibility that the implanted exogenous MSCs could engage the host's osteoprogenitor cells to form new bone tissue could open new perspectives for the tissue engineering approach to bone repair, including the opportunity of using allogenic cells combined with a temporary immunosuppressant therapy, stimulating the replacement of the exogenous cells with autologous cells.

The mouse model of experimental autoimmune uveitis, induced by immunization of mice with the retinal protein IRBP, was developed in our laboratory 20 years ago and published in 1988. Since that time it has been adopted by many investigators and has given rise to many studies that helped elucidate genetic influences, dissect the basic mechanisms of pathogenesis and test novel immunotherapeutic paradigms. The current overview will summarize the salient features of the experimental autoimmune uveitis model and discuss its mechanisms.

Bone marrow-derived mesenchymal stem cells (MSCs) are precursors of bone, cartilage and fat tissue. MSC can also regulate the immune response. For these properties, they are tested in clinical trials for tissue repair in combination with bioscaffolds or injected as cell suspension for immunosuppressant therapy. Experimental data, however, indicate that MSC can undergo or induce a tumorigenic process in determined circumstances. We used a modified model of ectopic bone formation in mice by subcutaneously implanting porous ceramic seeded with murine MSC. In this new model, host-derived sarcomas developed when we implanted MSC/bioscaffold constructs into syngeneic and immunodeficient recipients, but not in allogeneic hosts or when MSCs were injected as cell suspensions. The bioscaffold provided a tridimensional support for MSC to aggregate, thus producing the stimulus for triggering the process eventually leading to the transformation of surrounding cells and creating a surrogate tumor stroma. The chemical and physical characteristics of the bioscaffold did not affect tumor formation; sarcomas developed either when a stiff porous ceramic was used or when the scaffold was a smooth collagen sponge. The immunoregulatory function of MSC contributed to tumor development. Implanted MSC expanded clones of CD4+CD25+ T regulatory lymphocytes that suppressed host's antitumor immune response.

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