Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury

Classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) macrophages populate the local microenvironment after spinal cord injury (SCI). The former type is neurotoxic while the latter has positive effects on neuroregeneration and is less toxic. In addition, while the M1 macrophage response is rapidly induced and sustained, M2 induction is transient. A promising strategy for the repair of SCI is to increase the fraction of M2 cells and prolong their residence time. This study investigated the effect of M2 macrophages induced from bone marrow-derived macrophages on the local microenvironment and their possible role in neuroprotection after SCI. M2 macrophages produced anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor β and infiltrated into the injured spinal cord, stimulated M2 and helper T (Th)2 cells, and produced high levels of IL-10 and -13 at the site of injury. M2 cell transfer decreased spinal cord lesion volume and resulted in increased myelination of axons and preservation of neurons. This was accompanied by significant locomotor improvement as revealed by Basso, Beattie and Bresnahan locomotor rating scale, grid walk and footprint analyses. These results indicate that M2 adoptive transfer has beneficial effects for the injured spinal cord, in which the increased number of M2 macrophages causes a shift in the immunological response from Th1- to Th2-dominated through the production of anti-inflammatory cytokines, which in turn induces the polarization of local microglia and/or macrophages to the M2 subtype, and creates a local microenvironment that is conducive to the rescue of residual myelin and neurons and preservation of neuronal function.     

The role of the organ microenvironment in brain metastasis

More than 40% of patients with lung cancer and breast cancer develop brain metastasis. With improved local control and therapy of metastasis to visceral organs, the morbidity and mortality due to late diagnosed brain metastasis are projected to rise. The median survival for untreated patients is 1-2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy. The development of a relevant mouse model for the establishment and growth of brain metastasis has advanced our understanding of the biology and therapy of this most feared consequence of cancer. Injection of murine or human tumor cells into the internal carotid artery of mice produces experimental metastases in specific regions of the brain that are not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of metastatic tumor cells to exploit homeostatic mechanisms and proliferate. Immunohistochemical and morphometric analyses demonstrate that the density of blood vessels within experimental metastases in brains of mice or in clinical specimen of human lung cancer brain metastases is lower than that in the adjacent tumor-free brain parenchyma. However, brain metastasis-associated blood vessels are dilated and contain numerous dividing endothelial cells. Immunohistochemical analysis also reveals that tumor cells located less than 100 μm from a blood vessel are viable, whereas more distant tumor cells undergo apoptosis. Tumor cells within brain metastasis produce VEGF which induces permeability in adjacent vessels. The BBB in metastases that are larger than 0.25 mm in diameter is leaky. Metastases in the brain are resistant to chemotherapeutic drugs. The venerable "seed and soil" hypothesis suggests that the outcome of metastasis depends on the interaction between unique tumor cells and the specific organ microenvironment. The demonstration that activated astrocytes whose physiological role is to protect neurons from toxic substances can be exploited by tumor cells for protection from chemotherapeutic drugs suggests new approaches to the treatment of this fatal disease.     

Immune cell infiltration of primary and metastatic lesions: mechanisms and clinical impact

The infiltration of tumors and their metastases by hematopoietic cells can contribute both positively and negatively to tumor growth, invasion, and patient outcomes. These differing outcomes are associated with both tumor heterogeneity and the diversity of leukocytes infiltrating neoplastic lesions. Tumors infiltration by histiocytes (macrophages and dendritic cells (DCs)) is associated with poor clinical outcomes, although infiltration by a subset of DCs is related to improved outcomes. T-cell infiltration of tumors and metastases are surrogates for positive outcomes, although subset analysis suggests that not all infiltrating T-cells have this potential. Overall, tumor infiltration by CD8(+) T-cells is associated with a positive outcome, while the frequency of infiltrating CD4(+) cells may be a negative predictor. In addition to tumor infiltration by macrophages and T-cells, recent studies have shown that myeloid-derived suppressor cells (MDSCs), also infiltrate tumors, inhibiting T-cell and DC number and function and facilitate tumor growth, angiogenesis, and metastasis. In summary, hematopoietic cell infiltration of tumors can regulate tumor progression and provide a useful diagnostic surrogate. Further, strategies focused on the manipulation of cellular infiltration via cellular, gene and molecular immunotherapies have the potential to provide a novel target for adjuvant therapy.     

Aberrant DNA methylation profile in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a notoriously lethal epithelial cancer originating from the biliary system. As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage, the disease leads to a fairly poor prognosis. As the incidence of CCA is increasing, although the mortality rate remains stable, and few other definite etiologies have yet to be established, renewing our knowledge of its fundamental carcinogenesis is advisable. The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA. This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA.     

Tumor dormancy due to failure of angiogenesis: role of the microenvironment

Tumor progression is dependent on a number of sequential steps, including initial recruitment of blood vessels (i.e., angiogenic switch). Failure of a microscopic tumor to complete one or more of these early steps may lead to delayed clinical manifestation of the cancer. In this review we summarize some of the clinical and experimental evidence suggesting that microscopic human cancers can remain in an asymptomatic, non-detectable, and occult state for the life of a person or animal. We present three clinical cases where tumors present shortly after an accidental trauma in otherwise healthy individuals. We also review current experimental human tumor dormancy models with special emphasis on the angiogenic switch which closely recapitulates clinically observed delay in tumor recurrence.     

肝星状细胞与肿瘤肝转移的研究进展

肝脏是人体各类恶性肿瘤易于发生转移的部位,而肝星状细胞（HSC）在肿瘤肝转移中扮演着极为重要的角色。HSC能够促进和构成肿瘤细胞肝转移的微环境,肿瘤细胞又诱导HSC活化,活化的HSC又反作用于肿瘤细胞促其生长,两者双向作用呈现级联扩大效应,最终促进肿瘤侵袭、转移及生长。     

A novel mouse model of gastric cancer with human gastric microenvironment

Mouse models play an irreplaceable role in the in vivo research of human gastric cancer. In this study, we developed a novel human Gastric tissue-derived Orthotopic and Metastatic (GOM) mouse model of human gastric cancer, in which the human normal gastric tissues were implanted subcutaneously into immunodeficient mice to create a human gastric microenvironment. Then, human gastric cancer cells were injected into the implants. GOM model could mimic the interactions between human gastric microenvironment and human gastric cancer cells, which help exhibit the real characteristics of tumor cells, and finally mimic the clinical-like tumor proliferation and metastases of human beings.     

Towards a new age in the treatment of multiple myeloma

Multiple myeloma (MM) is an incurable disease characterized by the proliferation of end-stage B lymphocytes (plasma cells, PCs). As a consequence of myeloma growth in the bone marrow, a number of signaling pathways are activated that trigger malignant PC proliferation, escape from apoptosis, migration, and invasion. Thanks to new insights into the molecular pathogenesis of MM, novel approaches aimed at targeting these abnormally activated cascades have recently been developed and others are under study. These strategies include the inhibition of membrane receptor tyrosine kinases, inhibition of the proteasome/aggresome machinery, inhibition of histone deacetylases, inhibition of farnesyltransferases, targeting of molecular chaperones, and others. We will herein review and discuss these novel biological approaches with particular emphasis on those based on biochemical pathways which drive cell signaling. By providing the rationale for innovative therapeutic strategies, the above mechanisms represent targets for new compounds being tested in the management of this disease.     

The influence of different microenvironments on melanoma invasiveness and microcirculation patterns: an animal experiment study in the mouse model

Object To investigate the influence of different microenvironments on tumor microcirculation patterns and invasiveness capability. Methods Melanoma B16 cells were injected into the abdominal cavity and skeletal muscle of C57 mice synchronously. CK-18 expression in melanoma was assessed to distinguish the malignant phenotype of tumors in the abdominal cavity from that in the skeletal muscle. HIF-1α, MMP-2 and MMP-9 expression and mRNA levels of MMP-2 and MMP-9 was detected to compare the mRNA levels of MMP-2 and MMP-9 from the two microenvironments. Cells positive for each immunohistochemical stain and the vessels representative of each type of microcirculation pattern were counted in two microenvironments. Results CK-18 and HIF-1α expression of melanoma were significantly higher in the skeletal muscle than in the abdominal cavity (P < 0.05). Compared with the abdominal cavity, melanoma cells in the skeletal muscle overexpressed MMP-2 and MMP-9 (P < 0.05). Real time-PCR results also showed that MMP-2 and MMP-9 mRNA levels of melanoma were higher in the skeletal muscle than in the abdominal cavity (P < 0.05). VM channels and endothelium-dependent vessels were the major microcirculation pattern in the skeletal muscle and in the abdominal cavity, respectively. Conclusion Different microenvironments affect invasiveness and blood supply patterns of melanoma. Baocun Sun, Shiwu Zhang and Danfang Zhang are equally contributed for this work.