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PubMed2004

Biologic therapy for brain cancers--based on cellular and immunobiology.

The overall goal of our research projects is to develop effective immunotherapeutic regimens, particularly combining vaccine and gene therapy/ cell therapy strategies. For the development of clinically effective immunotherapy for brain cancers, the following issues are considered to be particularly important: 1) Induction of effective immune responses against tumors (afferent arm of the immune response), 2) Delivery of immune effector cells to the target tumor sites and maintaining the activity of the effector cells (efferent arm), 3) For specific and safe immunotherapy, specific brain tumor rejection antigens have to be identified, 4) Feasibility, safety and efficacy need to be tested in a series of clinical trials. The following presentation summarizes my research projects and demonstrates how each plan will fit in the whole schema of designing successful immunotherapeutic strategies for brain cancers. In this presentation, I would like to focus on our clinical and basic studies related to the vaccine strategies for patients with glioma, and modulation of tumor-microenvironment using bone-marrow derived stroma cells as vehicles for cytokine- gene delivery.

Biological Therapy↗
PubMed2004

Selective growth of epithelial basal cells from human prostate in a three-dimensional organ culture.

BACKGROUND: A three-dimensional organotypic culture method has been developed for selectively growing epithelial basal cells from human benign prostate. METHODS: Tissue fragments were cultured on sponges for several weeks and the viability of luminal and basal epithelium and cellular responses to 4,5alpha-dihydrotesterone (DHT) stimulation were studied. RESULTS: The gland tissue could be successfully maintained showing preservation of ducts and lobules as in vivo. Without DHT, a progressive hyperplasia of basal cells was observed: these cells proliferated with retention of the lumen or forming nests with squamous differentiation, lining the surface of the fragment and migrating to the underlying sponge. In contrast, secretory cells disappeared. Epithelial cells isolated from long-term cultures showed a typical basal cell-immunophenotype. DHT-treated tissues maintained a much higher percentage of luminal cells than untreated tissues. CONCLUSIONS: These systems allow the study of proliferation and differentiation of basal cells within their natural microenvironment as well as prostate pathobiology.

Cell Differentiation↗
PubMed1977

Morphological investigation on phenylhydrazine-induced erythropoiesis in the adult mouse liver.

In adult mice suffering from a phenylhydrazine (PHZ)-induced hemolytic anemia, erythropoietic islands were observed in the liver. These islands were studied with the light and electron microscope. Within two days after the beginning of four daily injections of PHZ, erythoid elements appeared in the sinusoids and central veins. A maximum number of erythroblasts was found on day 7. Light and electron microscopic observations revealed that the erythropoietic islands consisted of centrally located macrophages(CM) with a Kupffer cell-like morphology, surrounded by erythroblasts, which were often of the same maturation stage. CM in central veins (CM-V) and in sinusoids (CM-S) were found to have a different morphology. The CM-V phagocytized less circulating red blood cells and were in contact with a smaller number of erythroblasts. Furthermore, the contact areas between erythroblasts and CM-S extended for a much longer distance than those between erythroblasts and CM-V. The progenitor cell for the CM-V is most likely a monocyte, since cells which were morphologically determined as monocytes were found to appear on the first day of the PHZ treatment and differentiated into macrophages within about 2 days. The origin of the CM-S population was less clear, but could be monocytic as well. These data are tentatively explained as a migration of a progenitor of a cellular component of the erythroid micro-environment into the liver after appropriate stimuli. In contrast to fetal liver erythropoiesis, erythroblasts in the adult liver occurred only incidentally extrasinusoidally. Furthermore, specialized membrane contacts between erythroblasts and CM or hepatocytes could not be observed in adult liver. Ferritin could not be detected on the erythroid cell membrane or located in coated vesicles. Also, no ferritin could be observed within or attached to the finger-like processes of CM. The observations suggest that the coated vesicles in erythoid elements are partly exocytotic vesicles and are not specific for ferritin transport. The morphological aspects of PHZ-induced extramedullary erythropoiesis is discussed in relation to the hemopoietic microenvironment.

Animals↗
PubMed2006

The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome.

Functional diffusion map (fDM) has been recently reported as an early and quantitative biomarker of clinical brain tumor treatment outcome. This approach spatially maps and quantifies treatment-induced changes in tumor water diffusion values resulting from alterations in cell density/cell membrane function and microenvironment. This current study was designed to evaluate the capability of fDM for preclinical evaluation of dose escalation studies and to determine if these changes were correlated with outcome measures (cell kill and overall survival). Serial T2-weighted were carried out on rodents with orthotopically implanted 9L brain tumors receiving three doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (6.65, 13.3, and 26.6 mg/kg, i.p.). All images were coregistered to baseline T2-weighted images for fDM analysis. Analysis of tumor fDM data on day 4 posttreatment detected dose-dependent changes in tumor diffusion values, which were also found to be spatially dependent. Histologic analysis of treated tumors confirmed spatial changes in cellularity as observed by fDM. Early changes in tumor diffusion values were found to be highly correlative with drug dose and independent biologic outcome measures (cell kill and survival). Therefore, The fDM imaging biomarker for early prediction of treatment efficacy can be used in the drug development process.

Animals↗
PubMed1999

TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation.

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4(+) T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4(+) T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4(+) T cell responses that produce normal levels of interferon gamma, suggesting a CD40L/CD40-independent mechanism of CD4(+) T cell priming that to date has not been elucidated. Here we show that CD4(+) T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4(+) T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4(+) T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention.

Amino Acid Sequence↗
PubMedDate not supplied

Recent progress in understanding the relationships among aging, replicative senescence, cell turnover and cancer.

The link between aging and cancer is more than just the increasing accumulation of mutations with time. Recent research provides evidence that senescent cells are not merely passive bystanders, but may promote cancer through degradation of the tissue microenvironment. Another critical factor in the relationship between aging and cancer is p53 function; its activity level is apparently finely tuned to suppress cancer while regulating both apoptosis and the replacement of damaged cells through stem cell proliferation. The deacetylase activity of the sir2 gene product plays a role in longevity regulation in invertebrates, and also regulates p53 function in mammals, implying yet another link between aging and cancer in mammals.

Aging↗
PubMed1997

Therapy of radiation injury.

It is apparent from preclinical and clinical research to date that continued evaluation of new and alternative treatment strategies is required to eliminate the obligate periods of neutropenia and thrombocytopenia after acute high-dose irradiation. Future treatment strategies may involve new combinations of cytokines to affect hematopoietic stem cell proliferation and "engineered" cellular grafts to provide short-term in vivo expansion of neutrophils and platelets in an effort to bridge the cytopenic gap until endogenous or transplanted stem cells regenerate the hematopoietic and immune systems. Cytokine-mobilized peripheral blood and cord blood will provide alternative sources of allogeneic stem and progenitor cells in support of primary engraftment, delayed engraftment or secondary failure of the initial graft, as well as starting populations for various ex vivo expansion protocols. Further insights into the relative quality of stem cell populations and the factors that regulate their survival and self renewal, and the identification and roles of adhesion molecules in stem cell mobilization, engraftment, and interaction with the adult marrow microenvironment will provide the basis for future treatment strategies for the radiation-induced hematopoietic syndrome. As our ability to treat the hematopoietic syndrome improves, damage to other organ systems such as the skin, lung, and/or gastrointestinal tissue will emerge as dose-limiting. At the same time, the characterization of receptors for inflammatory cytokines, cytokine receptor antagonists, and anti-endotoxin antibodies has allowed significant insights into the mechanisms and pathogenesis of sepsis. However, translation of this knowledge into a treatment modality for septic patients is precluded by the lack of any clear-cut beneficial effect from the many clinical trials. The research and clinical results presented in this volume and recent conferences reflect the body of knowledge that will lead to further developments in assessment, prophylaxis, and treatment of radiation injuries in the areas of infectious disease and the hematopoietic, gastrointestinal, and cutaneous syndromes.

Acute Disease↗
PubMed2006

Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

Adenomatous Polyposis Coli↗
PubMed1999

Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium.

The Na+/H+ exchanger NHE1 isoform is an integral component of cardiac intracellular pH homeostasis that is critically important for myocardial contractility. To gain further insight into its physiological significance, we determined its cellular distribution in adult rat heart by using immunohistochemistry and confocal microscopy. NHE1 was localized predominantly at the intercalated disk regions in close proximity to the gap junction protein connexin 43 of atrial and ventricular muscle cells. Significant labeling of NHE1 was also observed along the transverse tubular systems, but not the lateral sarcolemmal membranes, of both cell types. In contrast, the Na+-K+-ATPase alpha1-subunit was readily labeled by a specific mouse monoclonal antibody (McK1) along the entire ventricular sarcolemma and intercalated disks and, to a lesser extent, in the transverse tubules. These results indicate that NHE1 has a distinct distribution in heart and may fulfill specialized roles by selectively regulating the pH microenvironment of pH-sensitive proteins at the intercalated disks (e.g., connexin 43) and near the cytosolic surface of sarcoplasmic reticulum cisternae (e.g., ryanodine receptor), thereby influencing impulse conduction and excitation-contraction coupling.

Animals↗
PubMed2000

Modulation of leukocyte behavior by an inflamed extracellular matrix.

Inflammation is a response of the immune system to foreign insult or physical damage. Various cellular and humoral components of the immune system are recruited from the vascular system and are translocated through endothelium, and into extracellular matrix (ECM) compartments of inflamed tissues. This translocation is orchestrated by various types of accessory signals, in the form of soluble or complexed molecules, which evoke remarkable transitions in leukocyte activities. Recruited inflammatory cells give rise to mechanisms of migration, including the secretion of enzymes and other pro-inflammatory mediators and the alteration of their adhesive contacts with the ECM. Hence, migrating cells secrete enzymes, chemokines, and cytokines which interact with the ECM, and thereby, provide the cells with intrinsic signals for coordinating their responses. Resultant products of enzymatic modifications to the ECM microenvironment, such as cytokine- and ECM-derived molecules, may be also part of a cell-signaling mechanism that provides leukocytes with information about the nature of their inflammatory activity; such a mechanism may give the immune system data that can be cognitively interpreted for consequential activities. This article reviews the findings that support this notion and describe the dynamic interactions between participants of the inflammatory processes.

Animals↗
PubMed1997

Beta-1-integrin expression in adult acute lymphoblastic leukemia: possible relationship with the stem cell antigen CD34.

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

Adult↗
PubMedDate not supplied

Hemopoietic progenitor cells in atopic dermatitis skin lesions.

We have recently shown the expression of lymphoid early developmental markers, including CD104, Thy 1, CD1a, Pgp-1 and TdT, by the cells constituting atopic dermatitis skin infiltrates. To further characterize the cellular phenotypes we used an indirect immunoperoxidase assay to analyze sections from two atopic dermatitis lesion skin biopsies using the following as first step monoclonal antibodies (MAB): anti-CD34, CD2, CD5 and CD7. CD34+ mononuclear cells and endothelial cells were identified. A strong immunoreaction was observed for the T-lineage marker CD2 and CD5, but a poor reaction, if any, was seen for the CD7. Since CD34+ marrow and blood cells are currently believed to be the major source of the hemopoietic precursors, our data provide further substantial evidence supporting the hypothesis that the atopic dermatitis skin cell infiltrate represents an ongoing T-lineage in situ differentiation process regulated by the skin epithelial microenvironment. The observed defective expression of the CD7 antigen requires further investigation for its confirmation as a possible constant feature in atopic dermatitis.

Acute Disease↗
PubMed1983

Proposal for basic definitions in experimental hematology.

This paper is concerned with basic definitions of cellular stages, processes, and factors in the hemopoietic system from a physiological and operational point of view. In most instances it was also attempted to delineate the relationship between equivalent physiological and operational terms. Such physiological terms were defined for the hemopoietic system, hemopoietic stroma, cell compartment, stem cell, progenitor cell, precursor cell and end cell. The following operational terms were included: hemopoiesis repopulating cell, spleen colony forming unit, transient endogenous colony forming unit, antitheta-sensitive regulatory cell, erythropoietic burst forming unit, granulocyte-macrophage colony forming cell, and marrow fibroblastoid colony forming unit. Subsequently, the following processes were defined: differentiation, maturation, self-renewal, proliferation, regulation and cloning. Moreover, the meanings of macro- and microenvironment of hemopoiesis were explained and definitions of hemopoietic hormones, regulatory cells, such as helpers and suppressors were proposed. Finally, such operational terms were precised as colony stimulating activity, colony stimulating factor, conditioned medium and underlayer. It is hoped that the proposed definitions will be helpful for those readers unacquainted with the specific terminology in the field of experimental hematology and that they will serve as a preliminary step towards international standardization of the terminology in this field.

Animals↗
PubMed1994

Cytokine networks in solid human tumors: regulation of angiogenesis.

The isolation, purification, and molecular cloning of an increasing number of cytokines and their receptors have allowed major advances in our understanding of the relevance of these proteins to the pathobiology and treatment of such human diseases as neoplasia. Cytokines produced by the multiple cell types present within the microenvironment of solid tumors from a complex, dynamic network, in which they have overlapping properties, induce other cytokines and alter the expression of soluble and cell surface-bound cytokine receptors. A broad number of such intratumoral cytokines have multiple effects on tumor progression. These include direct and indirect effects both on tumor cell growth and metastatic behaviors and on such cells in the stromal compartment as fibroblasts, infiltrating immune cells, and endothelial cells in the microvasculature. Here, we review the sites of production and multifaceted role of several key cytokines in the stimulation of a new blood supply within growing neoplasms. The clinical implications and new therapeutic targets suggested by this rapidly emerging picture of the cellular and molecular mechanisms subserving tumor angiogenesis are also discussed.

Cytokines↗
PubMed2005

Another dimension to calcium signaling: a look at extracellular calcium.

Cell biologists know the calcium ion best as a vital intracellular second messenger that governs countless cellular functions. However, the recent identification of cell-surface detectors for extracellular Ca(2+) has prompted consideration of whether Ca(2+) also functions as a signaling molecule in the extracellular milieu. The cast of Ca(2+) sensors includes the well-characterized extracellular-Ca(2+)-sensing receptor, a G-protein-coupled receptor originally isolated from the parathyroid gland. In addition, other receptors, channels and membrane proteins, such as gap junction hemichannels, metabotropic glutamate receptors, HERG K(+) channels and the receptor Notch, are all sensitive to external [Ca(2+)] fluctuations. A recently cloned Ca(2+) sensor (CAS) in Arabidopsis extends this concept to the plant kingdom. Emerging evidence indicates that [Ca(2+)] in the local microenvironment outside the cell undergoes alterations potentially sufficient to exert biological actions through these sensor proteins. The extracellular space might therefore constitute a much more dynamic Ca(2+) signaling compartment than previously appreciated.

Animals↗
PubMed1998

The neuro-immunological interface in an evolutionary perspective: the dynamic relationship between effector and recognition systems.

The evolutionary perspective indicates that an immune-neuroendocrine effector system integrating innate immunity, stress and inflammation is present in invertebrates. This defense network, centered on the macrophage and exerting primitive and highly promiscuous recognition units, is very effective, ancestral and appears to have been conserved throughout evolution from invertebrates to higher vertebrates. It would seem that there was a "big bang" in the recognition system of lower vertebrates, and T and B cell repertoires, MHC and antibodies suddenly appeared. We argue that this phenomenon is the counterpart of the increasing complexity of the internal circuitry and recognition units in the effector system. The immediate consequences were a progressive enlargement of the pathogen repertoire and new problems regarding self/not-self discrimination. Probably not by chance, a new organ appeared, capable of purging cells able of excessive self recognition. This organ, the thymus, appears to be the result of a well known evolutionary strategy of re-using pre-existing material (neuroendocrine cells and mediators constituting the thymic microenvironment). This bricolage at an organ level is similar to the effect we have already described at the level of molecules and functions of the defense network, and has a general counterpart at genetic level. Thus, in vertebrates, the conserved immune-neuroendocrine effector system remains of fundamental importance in defense against pathogens, while its efficiency has increased through synergy with the new, clonotipical recognition repertoire.

Animals↗
PubMed1986

Neuroendocrine control of secretion in pancreatic and parotid gland acini and the role of Na+,K+-ATPase activity.

The results of our investigations into the localization of Na+,K+-pump activity in pancreatic and parotid acinar cells and the effects of hormones and neurotransmitters on pump turnover can be integrated with data on other aspects of stimulus-response coupling to construct models of the neurohumoral control of protein, fluid, and electrolyte secretion (Fig. 23). In both tissues, Ca2+ and cyclic AMP serve as intracellular messengers. In pancreatic acinar cells, the Ca2+-dependent pathway activated by the occupation of CCK or cholinergic receptors provides the primary stimulus for digestive enzyme secretion. Cyclic AMP plays a comparatively minor role; VIP and secretin are much less effective stimulators of protein secretion. Conversely, cyclic AMP levels in parotid acinar cells, which are modulated primarily through occupation of beta-adrenergic receptors, are a major determinant of enzyme secretion. Activation of the Ca2+-dependent pathway by cholinergic or alpha-adrenergic agonists or substance P is less important. The presence of dual control processes in each gland suggests that the observed differences in effectiveness of cyclic AMP- versus Ca2+-dependent secretagogues may reflect not different mechanisms, but rather a shift in the relative emphasis placed on each pathway. This emphasis could conceivably result from subtle variations in the interaction between cellular protein kinases and phosphatases and their phosphoprotein substrates. Electrolyte secretion, on the other hand, appears to involve both discrete and common entities. In pancreatic acinar cells from rodent species, cholinergic or CCK receptor occupancy elicits a Ca2+-dependent increase in the open-state probability of nonselective cation channels in the basolateral plasma membrane. The resultant influx of Na+ and efflux of K+ is most probably the factor which activates Na+, K+-pumps. Based on electron probe studies of the effects of cholinergic agonists on acinar cell Na+ and K+ contents discussed earlier, a transient reduction in the intracellular K+/Na+ ratio of up to 4-fold may occur. A shift of this magnitude in the cytoplasmic microenvironment of the Na+, K+-pump clearly would have a stimulatory influence (see discussion by Jorgensen, 1980). In addition, Ca2+ itself may have direct effects on Na+,K+-pump activity. Calcium at levels much above 1 microM progressively inhibits Na+,K+-ATPase activity (Tobin et al., 1973; Yingst and Polasek, 1985). In unstimulated guinea pig pancreatic acinar cells, Ca2+i measured by quin-2 fluorescence was 161 +/- 13 nM (Hootman et al., 1985a) which increased to a maximal concentration of 803 +/- 122 nM following CCh stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2024

The burgeoning spatial multi-omics in human gastrointestinal cancers.

The development and progression of diseases in multicellular organisms unfold within the intricate three-dimensional body environment. Thus, to comprehensively understand the molecular mechanisms governing individual development and disease progression, precise acquisition of biological data, including genome, transcriptome, proteome, metabolome, and epigenome, with single-cell resolution and spatial information within the body's three-dimensional context, is essential. This foundational information serves as the basis for deciphering cellular and molecular mechanisms. Although single-cell multi-omics technology can provide biological information such as genome, transcriptome, proteome, metabolome, and epigenome with single-cell resolution, the sample preparation process leads to the loss of spatial information. Spatial multi-omics technology, however, facilitates the characterization of biological data, such as genome, transcriptome, proteome, metabolome, and epigenome in tissue samples, while retaining their spatial context. Consequently, these techniques significantly enhance our understanding of individual development and disease pathology. Currently, spatial multi-omics technology has played a vital role in elucidating various processes in tumor biology, including tumor occurrence, development, and metastasis, particularly in the realms of tumor immunity and the heterogeneity of the tumor microenvironment. Therefore, this article provides a comprehensive overview of spatial transcriptomics, spatial proteomics, and spatial metabolomics-related technologies and their application in research concerning esophageal cancer, gastric cancer, and colorectal cancer. The objective is to foster the research and implementation of spatial multi-omics technology in digestive tumor diseases. This review will provide new technical insights for molecular biology researchers.

Humans↗