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PubMed1995

Modification of tumor microenvironment by cytokine gene transfer.

The tumor microenvironment is determined by the interactions between host and tumor cells, a process in which cytokines play a major role. We have used retroviral vectors to insert and express cytokine genes in tumor cells so as to induce predictable changes in the host cells that infiltrate tumors. This frequently caused changes in tumor cell phenotype through autocrine/intracrine pathways. We reasoned that cytokine-induced alterations in tumor cell phenotype and/or in infiltrating host cells might alter the in vitro and in vivo cellular response to irradiation. In the present paper we document some of the effects of expression of interleukin-6 (IL-6) and IL-7 genes in tumor cells in this regard. The studies support the hypothesis that cytokines may play a role in determining both intrinsic tumor radioresponsiveness and the tumor microenvironment and in these ways may influence in vivo tumor irradiation responses. Possible cytokine gene-mediated approaches to radiotherapy cancer are discussed.

Animals↗
PubMed1995

A multivariate study of non Hodgkin's lymphoma involving proliferation, apoptosis, bcl-2 and the microenvironment.

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

Apoptosis↗
PubMed2005

[Effects of Lycium barbarum polysaccharide on tumor microenvironment T-lymphocyte subsets and dendritic cells in H22-bearing mice].

OBJECTIVE: To study the effects of Lycium barbarum polysaccharide (LBP) on tumor microenvironment T-lymphocyte subsets and dendritic cells in H22-bearing mice and the mechanisms for intervention of tumor immune escape by LBP. METHODS: H22-bearing mice were given LBP orally for two weeks. T-lymphocyte subsets and the phenotypes of dendritic cells in tumor-infiltrating lymphocytes (TIL) were detected by flow cytometry (FCM). RESULTS: LBP could significantly increase the numbers of CD4(+) and CD8(+) T cells in TIL as compared with those in model control group (P<0.05). In model control group, the number of dendritic cells in tumor microenvironment decreased markedly, while in LBP-treated group, the increased number of dendritic cells and B7-1 expression were observed, but there were no significant differences between these two groups. CONCLUSION: LBP has anti-tumor effect probably by increasing the numbers of CD4(+) and CD8(+) T cells in TIL to relieve the immunosuppression and enhance the anti-tumor function of the immune system. But whether LBP can recover the phenocyte and function of dendritic cells in H22-bearing mice should be further studied.

Animals↗
PubMed2001

The Peyer's patch microenvironment suppresses T cell responses to chemokines and other stimuli.

Immunosurveillance of mucosal sites presents immune cells with challenges not encountered in the periphery. T cells in the gut must distinguish enteric pathogens from innocuous non-self Ag derived from food or commensal bacteria. The mechanisms that regulate T cells in the gut remain incompletely understood. We assessed the effect of the Peyer's patch microenvironment on T cell responses to chemokines. Chemokines are believed to play an important role during T cell priming by facilitating T cell migration into and within lymphoid tissues as well as T cell encounter and interaction with APCs. We found a profound suppression of chemokine-stimulated T cell chemotaxis and actin polymerization in Peyer's patch relative to lymph node. Chemokine hyporesponsiveness is imposed upon T cells within hours of their entry into Peyer's patches and is reversed following their removal. Suppression was not restricted to chemokine stimulation, as T cell responses to Con A and PMA were also suppressed. The global nature of this defect is further underscored by an impairment in calcium mobilization. Evidence indicates that a soluble factor contributes to this hyporesponsiveness, and comparison of Peyer's patches and lymph nodes revealed striking differences in their chemokine and cytokine constitution, indicating a marked Th2 bias in the Peyer's patches. The role of the Th2 microenvironment in mediating suppression is suggested by the ability of Nippostrongylus brasiliensis to elicit hyporesponsiveness in lymph node T cells. The suppressive milieu encountered by T cells in Peyer's patches may be critical for discouraging undesired immune responses and promoting tolerance.

Actins↗
PubMed2005

Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.

B cell immunotherapy has emerged as a mainstay in the treatment of lymphomas and autoimmune diseases. Although the microenvironment has recently been demonstrated to play critical roles in B cell homeostasis, its contribution to immunotherapy is unknown. To analyze the in vivo factors that regulate mechanisms involved in B cell immunotherapy, we used a murine model for human CD20 (hCD20) expression in which treatment of hCD20(+) mice with anti-hCD20 mAbs mimics B cell depletion observed in humans. We demonstrate in this study that factors derived from the microenvironment, including signals from the B cell-activating factor belonging to the TNF family/BLyS survival factor, integrin-regulated homeostasis, and circulatory dynamics of B cells define distinct in vivo mechanism(s) and sensitivities of cells in anti-hCD20 mAb-directed therapies. These findings provide new insights into the mechanisms of immunotherapy and define new opportunities in the treatment of cancers and autoimmune diseases.

Animals↗
PubMed2005

Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells.

The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-gamma. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45(+) leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-alpha. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4(+) effector memory T cell. We conclude that quiescent CD4(+) effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-gamma, leading to tumor cell eradication.

Animals↗
PubMed2004

[P450Arom and estrogenic microenvironment of eutopic endometria in endometriosis].

BACKGROUND: Endometriosis, a common gynecologic disorder characterized by endometrial glands and stroma outside the uterus, is diagnosed by direct visualization of peritoneal and ovarian implants during laparoscopy. AIM: To study the estrogenic microenvironment in eutopic endometria of women with and without endometriosis. PATIENTS AND METHODS: Eutopic endometria, obtained during laparoscopy from 23 women with endometriosis and 20 fertile cyclic women undergoing tubal sterilization, was studied. P450Arom mRNA expression (RT-PCR) was measured. Also, P450Arom activity was assessed measuring testosterone conversion to estradiol and the concentration of this last hormone in cultured endometrial explants. RESULTS: Age and body mass index was similar in both groups studied. Seventy nine percent of endometria from women with endometriosis and in 29.4% from control group expressed P450Arom mRNA (p <0.01). The intensity of the band was higher in secretory endometria from women with endometriosis when compared to controls (p <0.01), but it was similar during the proliferative phase. Estradiol secretion to the culture media by proliferative endometria explants from women with endometriosis was 3-fold higher than secretory endometria (p <0.01) and endometria from control women in both phases. P450Arom activity, in the presence of testosterone, was 7-fold higher in endometrial cultures from women with endometriosis, when compare with the basal culture (p <0.01). However, in endometrial explant cultures from control women, this activity was not statistical different. CONCLUSIONS: These results indicate that in women with endometriosis, the microenvironment in the endometria is estrogenic as a consequence of an increased expression and activity of the P450Arom.

Aromatase↗
PubMed2006

Identification of fibroblast heterogeneity in the tumor microenvironment.

Tumors are unorganized organs that contain many different cell types. In the recent years, many studies have reported that primary tumors contain fibroblasts/myofibroblasts (carcinoma-associated fibroblasts), mesenchymal cells such as pericytes/mural cells and other vascular smooth muscle cells. Several different markers are used routinely to identify carcinoma-associated fibroblasts (CAFs) such as alpha-smooth muscle actin (alpha-SMA), vimentin, S100A4 protein/fibroblast specific protein-1 (FSP1) and type I collagen. Likewise markers such as platelet derived growth factor receptor-beta (PDGFRbeta) and NG2 chondroitin sulfate proteoglycan (NG2) are used to identify mesenchymal cells such as pericytes and other vasculature associated smooth muscle cells. It is still unknown whether these markers overlap with each other or identify a unique population of cells within the tumor microenvironment. Therefore in the present study we utilized two different mouse models of cancer, the Rip1Tag2 mice that develop progressive pancreatic cancer and an orthotopic 4T1 breast cancer model, to study the overlap between six different mesenchymal markers commonly used in mouse cancer research. Our study demonstrates that among all the markers, S100A4/FSP1 identifies a unique population of fibroblasts with minimal overlap with markers for alphaSMA, PDGFRbeta and NG2. Vimentin and type I collagen are not specific markers for fibroblasts in these tumors. alphaSMA, PDGFRbeta and NG2 significantly overlap with each other in identifying a mixed population of fibroblasts (activated or resting), myofibroblasts, pericytes and vascular smooth muscle cells. Collectively, this study demonstrates that tumor microenvironment associated fibroblasts are a heterogeneous population and thus, the use of alphaSMA or vimentin as the only markers will not identify all the CAFs.

Actins↗
PubMed2006

Hypoxic microenvironment as a cradle for melanoma development and progression.

Hypoxia-inducible factor (HIF)-1alpha, a global regulator of oxygen homeostasis, plays a crucial role in tumor cell adaptation to the hypoxic microenvironment through transcriptional regulation of its target genes. These genes in turn are involved in a plethora of biochemical as well as cell biological processes, including glucose metabolism, apoptosis and angiogenesis. In melanoma, HIF-1alpha has been implicated in tumor progression with effects upon metastasis and angiogenesis. However, its role in malignant transformation by oncogenes has not been described. Bedogni et al. (Cancer Cell 2005, 8:443-54) report that the hypoxic microenvironment in the skin contributes to melanocyte transformation and tumor growth induced by oncogenes Ras and Akt, which are frequently activated in melanoma. HIF-1alpha activity was found to be required in Akt-induced melanocyte transformation and tumor growth and it was suppressed greatly by mTOR inhibition with rapamycin. Since mTOR regulates HIF-1alpha expression and its transcriptional activity, rapamycin was proposed as a promising hypoxia-related therapeutic approach in melanoma treatment. This study sheds light upon the role of HIF-1alpha in the early stage of melanoma development and highlights the importance of the Akt-mTOR pathway in the regulation of HIF-1alpha.

Cell Hypoxia↗
PubMed1998

[Morphologic and functional features of hemopoietic microenvironment in acute lymphoblastic leukemia].

Data of the histological, ultrastructural and culture cell investigations of bone marrow microenvironment in 20 patients with acute lymphoblastic leukemia (ALL) are presented. Morphological and functional peculiarities of the patients' bone marrow stroma different from that in healthy subjects were identified. They included distorted histotopographic patterns of stroma-hemopoietic cell-to-cell interaction, obliteration of sinusoid counts, resorption on the sites of internal bone support structures, a changed stromal cells ratio, formation of reticular cell clusters in the subendosteal and perivascular bone marrow areas, fibroid centers, the presence of nuclear bodies in stromal cell nuclei and an intensified proliferation of stromal cell precursors in organ tissue cultures. Morphological and functional changes in bone marrow microenvironment were detected in ALL patients, which could have been caused both by malignant cell clones and stromal defects.

Adult↗
PubMed2000

Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment.

Evidence is accumulating that the adverse tumor microenvironment both modifies the malignant progression of tumor cells and contributes to chemotherapy and radiation resistance. We hypothesized that some of the effects on malignant progression are mediated through the transcriptional regulation of genes responsive to the stresses of the microenvironment, such as low oxygen or low glucose conditions. To determine epigenetic changes in gene expression that were consistent with that hypothesis, we used an in vitro subtractive hybridization method, representational difference analysis, to identify hypoxia-induced cDNAs from cultured human cervical epithelial cells. We identified 12 induced genes: two novel genes (HIG1 and HIG2), three genes known to be hypoxia-inducible (tissue factor, GAPDH, thioredoxin), and seven genes not previously identified as hypoxia-inducible [HNRNP(a1), ribosomal L7, annexin V, lipocortin 2, Ku(70), PRPP synthase, and acetoacetyl-CoA thiolase]. In cultured cells, HIG1 and HIG2 expression is induced by hypoxia and by glucose deprivation, but their expression is not induced by serum deprivation, UV, or ionizing radiation. The putative HIG1 and HIG2 open reading frames are expressed in cells, as confirmed by epitope tagging. In addition, tumor xenografts derived from human cervical cancer cells display increased expression of HIG1 and HIG2 when they are deprived of oxygen. Taken together, these data suggest a coordinated transcriptional response of eukaryotic cells to microenvironmental stresses found in the solid tumor.

Amino Acid Sequence↗
PubMed2000

Functional disturbances in hemopoietic microenvironment in various forms of myelodysplastic syndrome.

We studied the ability of stromal sublayer of long-term bone marrow cultures and peripheral blood macrophages from patients with various forms of myelodysplastic syndrome to maintain the growth of normal granulocyte-macrophage colony-forming units in mixed cultures. There were changes in the hemopoietic microenvironment in these patients: decreased cellularity of the bone marrow and impaired formation of sublayers in long-term bone marrow cultures, production of growth factors, maintaining the growth of normal granulocyte-macrophage precursors by stromal cells. Dysfunction of macrophages in the stromal microenvironment was probably related to the presence of pathological macrophages./Abstract>

Bone Marrow↗
PubMed2001

Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE.

To understand the molecular basis for the differences in receptor-binding activity of the three common human apolipoprotein E (apoE) isoforms, we characterized the microenvironments of their LDL receptor (LDLR)-binding regions (residues 136;-150). When present in dimyristoyl phosphatidylcholine (DMPC) complexes, the 22-kDa amino-terminal fragments (residues 1;-191) of apoE3 and apoE4 bound to the LDLR with approximately 100-fold greater affinity than the 22-kDa fragment of apoE2. The pK(a) values of lysines (K) at positions 143 and 146 in the LDLR-binding region in DMPC-associated 22-kDa apoE fragments were 9.4 and 9.9 in apoE2, 9.5 and 9.2 in apoE3, and 9.9 and 9.4 in apoE4, respectively. The increased pK(a) of K146 in apoE2 relative to apoE3 arises from a reduction in the positive electrostatic potential in its microenvironment. This effect occurs because C158 in apoE2, unlike R158 in apoE3, rearranges the intrahelical salt bridges along the polar face of the amphipathic alpha-helix spanning the LDLR-binding region, reducing the effect of the R150 positive charge on K146 and concomitantly decreasing LDLR-binding affinity. The C112R mutation in apoE4 that differentiates it from apoE3 did not perturb the pK(a) of K146 significantly, but it increased the pK(a) of K143 in apoE4 by 0.4 pH unit. This change did not alter LDLR-binding affinity. Therefore, maintaining the appropriate positive charge at the C-terminal end of the receptor-binding region is particularly critical for effective interaction with acidic residues on the LDLR.

Amino Acids↗
PubMed2001

Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis.

The outcome of cancer metastasis depends on multiple interactions (cross-talk) between selected metastatic cells and homeostatic mechanisms unique to some organ microenvironments. The organ microenvironment can influence the biology of cancer growth, angiogenesis, and metastasis in several different ways. Therapy of metastasis, therefore, should be targeted against metastatic tumor cells and the homeostatic factors that are favorable to metastasis, growth, and survival of the metastatic cells.

Antineoplastic Agents↗
PubMed2001

Effect of papaya seed extract on microenvironment of cauda epididymis.

AIM: To evaluate the effect of aqueous Carica papaya seed extract on microenvironment of cauda epididymis. METHODS: Adult male albino rats were intramuscularly administered with 0 (control) or 0.5 mg papaya seed extract/kg body weight for 7 days. Cauda epididymal tubular content was collected by micropuncture technique; epididymal luminal fluid and sperm pellets were separately analyzed. RESULTS: The results revealed that the extract treatment caused significant reduction, as compared with control, in total protein and sialic acid contents in both epididymal fluid and sperm pellet. As compared with control, significantly lowered acid phosphatase activity was recorded in sperm pellet but was higher in epididymal fluid after the treatment. The extract treatment also caused significant reduction in level of inorganic phosphorus in the epididymal fluid. CONCLUSION: It is concluded that the aqueous papaya seed extract alters cauda epididymal microenvironment.

Acid Phosphatase↗
PubMedDate not supplied

Cytokines and Immune Response in the Tumor Microenvironment.

SUMMARY: Over the last few decades a wealth of evidence has been gathered on the potential role that the immune system (IS) can play in the fight against cancer. Together with cell surface adhesion molecules, cytokines (CKs) mediate the activities of IS cells. Therefore, CK kinetics may represent a mirror of the immunologic phenomena occurring in the tumor microenvironment, where immune and malignant cells interact. Yet, CKs are currently used in a clinical setting to polarize the immune response against cancer. Despite the large amount of information available on IS physiology, little is known about the role of CKs in modulating the effectiveness of immunotherapy clinical trials aimed at the treatment of patients with cancer. This underscores our relative ignorance about the complex cascade of events that lead to tumor rejection. Here, we review the properties of some CKs believed to be particularly relevant to tumor immunology (i.e., interleukin [IL]-10, transforming growth factor-beta, interferon-gamma, IL-2, IL-4, and IL-12). We summarized the experience gained with these CKs in vitro, in animal models, and in human beings to illustrate the achievements, the controversies, and the challenges that characterize this fascinating field of oncology. In addition, we added a short section in which a broad view of CKs released in the tumor microenvironment is proposed to underline the variety of factors that contribute to the complexity of tumor-IS interactions.

Journal Article↗
PubMedDate not supplied

Cytokines and immune response in the tumor microenvironment.

Over the last few decades a wealth of evidence has been gathered on the potential role that the immune system (IS) can play in the fight against cancer. Together with cell surface adhesion molecules, cytokines (CKs) mediate the activities of IS cells. Therefore, CK kinetics may represent a mirror of the immunologic phenomena occurring in the tumor microenvironment, where immune and malignant cells interact. Yet, CKs are currently used in a clinical setting to polarize the immune response against cancer. Despite the large amount of information available on IS physiology, little is known about the role of CKs in modulating the effectiveness of immunotherapy clinical trials aimed at the treatment of patients with cancer. This underscores our relative ignorance about the complex cascade of events that lead to tumor rejection. Here, we review the properties of some CKs believed to be particularly relevant to tumor immunology (i.e., interleukin [IL]-10, transforming growth factor-beta, interferon-gamma, IL-2, IL-4, and IL-12). We summarized the experience gained with these CKs in vitro, in animal models, and in human beings to illustrate the achievements, the controversies, and the challenges that characterize this fascinating field of oncology. In addition, we added a short section in which a broad view of CKs released in the tumor microenvironment is proposed to underline the variety of factors that contribute to the complexity of tumor-IS interactions.

Cytokines↗
PubMed2001

Effect of bilateral testicular resection on thymocyte and its microenvironment in aged mice.

AIM: To observe the changes in thymocyte and its microenvironment in aged mice after bilateral testicular resection. METHODS: In male old mice, at the 25th day after testicular resection, the peripheral blood and thymus were collected. Blood and thymus suspension smears were prepared for quantitative histochemistry and immunohistochemistry study under light and electron microscopes. RESULTS: In testes resected mice the size and the weight of thymus were markedly increased. The demarcation between cortex and medulla was clear. The cortex was thickened and the cell density was increased. The ratio of cortex/medulla stereometry was increased. The total cell count, thymocyte count, the percentage of acid alpha-naphthyl acetate esterase (ANAE) positive thymocytes, nonlymphocytes and the rosette formation of macrophages and thymocytes were all increased. The thymocytes surrounded closely to the light thymic epithelial cells, dendritic cells or macrophages. The lymphocytes, particularly the ANAE positive lymphocytes of peripheral blood were increased. CONCLUSION: After bilateral testicular resection, the thymus of aged male mice showed morphological regeneration and the thymocytes and its microenvironment appeared to be definitely improved. It is suggested that testicular resection may improve immune function.

Aging↗