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Results for “Cellular Microenvironment”

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PubMed2002

Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory disease of the central nervous system that destroys myelin, oligodendrocytes, and axons. Since most of the lesions of multiple sclerosis are not remyelinated, enhancement of remyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of oligodendrocyte-producing cells into the lesions. We investigated the frequency distribution and configuration of oligodendrocytes in chronic lesions of multiple sclerosis to determine whether these factors limit remyelination. METHODS: Forty-eight chronic lesions obtained at autopsy from 10 patients with multiple sclerosis were examined immunocytochemically for oligodendrocytes and oligodendrocyte progenitor cells. Using confocal microscopy, we examined the three-dimensional relations between axons and the processes of premyelinating oligodendrocytes. RESULTS: Thirty-four of the 48 chronic lesions of multiple sclerosis contained oligodendrocytes with multiple extended processes that associated with demyelinated axons but failed to myelinate them. These axons were dystrophic and contained multiple swellings. In some regions, the densities of premyelinating oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent brain (23 per square millimeter). In the patients with disease of long duration (more than 20 years), there were fewer lesions with premyelinating oligodendrocytes (P<0.001). CONCLUSIONS: Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination.

Adult↗

PubMed2006

HIV-1 matrix protein p17 modulates in vivo preactivated murine T-cell response and enhances the induction of systemic and mucosal immunity against intranasally co-administered antigens.

HIV-1 p17 is a viral cytokine that acts on preactivated, but not on resting, human T cells promoting proliferation, proinflammatory cytokines release and HIV-1 replication, after binding to a cellular receptor (p17R). Here, we demonstrate that p17Rs are expressed on activated murine T cells, which respond to p17 stimulation similarly to their human counterpart. We developed a mouse model of abortive HSV-1 infection to induce T cell activation in vivo. Preactivated cells expressed p17Rs and were highly susceptible to p17 stimulation, which triggered proinflammatory cytokines release and promoted CD4+ T cell survival and expansion. Coculture of in vivo activated splenocytes with macrophages in the presence of p17 further increased their ability to produce IFN-gamma. The presence of macrophages and activated T cells at mucosal sites prompted us to investigate the immunomodulatory activities of p17 in vivo. Intranasal coadministration of p17 with beta-galactosidase (beta-gal) resulted in improved beta-gal specific cellular and humoral immune responses at systemic and mucosal levels. It is well established that HIV-1 replication is driven in an autocrine/paracrine manner by endogenously produced proinflammatory cytokines. Our results highlight the role of p17 in sustaining cellular activation and inflammation, thereby promoting a permissive microenvironment for HIV-1 replication. In addition, p17 is a promising candidate antigen, exhibiting immunomodulatory/adjuvant properties, that need to be exploited in the development of HIV/AIDS vaccines.

Adjuvants, Immunologic↗

PubMed2005

Bone turnover mediates preferential localization of prostate cancer in the skeleton.

Bone metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered PTH to induce bone turnover and increase marrow cellularity daily 1 wk before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 wk. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and tartrate-resistant acid phosphatase 5b and in the number of tartrate-resistant acid phosphatase-positive osteoclasts per millimeter of bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by 5-bromo-2'-deoxyuridine immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.

Acid Phosphatase↗

PubMed2026

ZUP1 as a Novel Potential Oncogenic Driver and Prognostic Biomarker in Breast Cancer.

INTRODUCTION: Breast cancer is one of the main causes of cancer death in women globally. Identifying new predictive markers and therapeutic targets is important for improving patient outcomes. Zinc finger-containing U-rich RNA-binding protein 1 (ZUP1) is an RNA-binding protein containing a zinc finger structure that has not been systematically analyzed in breast cancer research. MATERIALS AND METHODS: The study used data from 1,231 samples from the Cancer Genome Atlas (TCGA) database. The ZUP1 expression in tumor tissues and normal tissues was compared. Its predictive value was assessed using survival analysis and regression models. Its biological role was explored through gene functional analysis. The immune cell analysis method was used to study the tumor immune environment, and the drug susceptibility database was used to predict drug responses. Predictive models were also built and validated. RESULTS: ZUP1 expression was significantly higher in breast cancer tissues than in normal tissues. High expression of ZUP1 is related to advanced tumor stage and is an independent indicator of poor survival prognosis in univariate and multivariate analyses. Functional enrichment revealed that ZUP1 is closely linked to cell cycle progression, DNA replication, and the Fanconi anemia (FA) pathway. Immune infiltration analysis demonstrated a significant negative link between ZUP1 levels and the abundance of resting mast cells and activated NK cells. Furthermore, high ZUP1 expression was associated with increased sensitivity to several targeted therapies, including Nutlin-3a and PD-0325901. A clinically applicable nomogram combining ZUP1 expression with key clinical factors (age, stage, T, N, M) was developed to predict 3- and 5-year OS with good calibration and discrimination. DISCUSSION: Our study identifies ZUP1 as a potential oncogenic factor and a robust independent prognostic biomarker in breast cancer. Its involvement in critical cellular processes and modulation of the tumor immune microenvironment highlights its potential as a novel therapeutic target. Functional experiments, including immunohistochemical staining and CCK8 proliferation assays, further supported the oncogenic role of ZUP1. The established nomogram provides a valuable tool for personalized risk assessment and clinical decision-making. CONCLUSION: Our findings suggest that ZUP1 is a novel multifaceted biomarker with significant implications for personalized treatment strategies in breast cancer.

ZUP1↗

PubMed1994

Functional reconstitution of pharmacologically distinct subtypes of nucleoside transporters in liposomal membranes.

We examined the functional and pharmacological characteristics of liposome-reconstituted nucleoside transporter proteins obtained by detergent (octylglucoside) extraction from Ehrlich ascites tumor cell plasma membranes. Optimal reconstitution was achieved using a lipid composition of phosphatidylcholine, cholesterol, phosphatidylethanolamine and phosphatidylserine in a molar ratio of 33:33:26:8 and with a lipid-to-protein ratio of 30. This preparation had Km and Vmax values of 280 microM and 570 pmol/mg/sec, respectively, for the transporter-mediated uptake of [3H]uridine and bound 8.3 pmol of [3H]nitrobenzyl-thioinosine per milligram of protein. In general, the reconstituted system had kinetic and pharmacological characteristics comparable to those of the native membrane-located system, including an 80:20 ratio of nitrobenzylthioinosine-sensitive to -resistant [3H]uridine influx. The uridine translocation capacity of the optimally reconstituted system was 56 molecules per transporter per second compared with 104 molecules per transporter per second in intact cells, indicating that more than half of the inserted proteins were capable of mediating the influx of [3H]uridine (assuming that each functioning transporter was operating at optimal efficiency). Differences between the native and reconstituted transporters included the appearance of a [3H]uridine influx component (inhibited by adenosine) that was resistant to inhibition by R75231 (18%) and dipyridamole (10%). Dilazep was also significantly less effective in inhibiting the nitrobenzylthioinosine-sensitive transporter in the reconstituted preparations (IC50 = 41 nM) relative to that seen in intact Ehrlich cells (IC50 = 1.4 nM). These results suggest that inhibitor sensitivity may be a factor of the lipid microenvironment of the transporter or may involve other cellular components that could dissociate from the complex on detergent solubilization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

[The characteristics of the development of the immune function in the transplanted spleen of newborn mouse pups in recipients of different ages. 2. The effect of the thymus on the functional development of the transplant].

The effect of the neonatal thymus grafting or "Thymostimulin" administration on the cellularity, cell composition, immune, response to SRBC and proliferative activity of T- and B-cells in vitro were determined in neonatal spleen grafted CBA/Ca female mice of different ages. Analysis of the thymus graft effect on the T- and B-cells content in the spleen transplant from the adult and old recipients demonstrated no differences. The neonatal thymus grafting led to the essential increase of the immune response, spleen cellularity and to the diametrically opposed changing from negative to positive of the sign of the correlation coefficient between the T-cells content and the cellularity of the neonatal spleen in the old recipients. The similar effect of the neonatal thymus grafting was revealed in respect of correlative connection between content of the T-cells and PFCs in spleen grafted to the old recipients too. The "Thymostimulin" injection led only to the increase of the spleen transplant cellularity. These results suggests that the young thymic microenvironment is essential for the normal T-cells differentiation and for its normal function in the neonatal spleen transplant.

Adjuvants, Immunologic↗

PubMed2002

Tumor-induced death of immune cells: its mechanisms and consequences.

FasL is a death-inducing as well as pro-inflammatory molecule. The seemingly opposing consequences of Fas/FasL interactions appear to be dependent on the context of the tumor or tissue microenvironment. The term 'contextual' has been coined to describe cellular and molecular events that may be opposing, yet are mediated by the engagement of the same receptor-ligand pair. Because Fas is one of the death-inducing receptors, its ligand is dangerous. Hence, the availability of FasL for cross-linking of the receptor has to be extremely carefully regulated. Different levels of control appear to exist, some involving cell membrane-associated MMPs and others depending on cytokines released from neighboring cells. In tumors, which shape their microenvironment to make it unwelcome to immune effector cells, FasL is used to kill infiltrating cells without damage to the tumor, which develops multiple means of hiding/inhibiting the death pathway. On the other hand, in situations provoking inflammatory responses such as allograft rejection, infection, and tissue necrosis, FasL assumes the role of attractant for inflammatory cells. In these situations, FasL acts in conjunction with other cytokines, and its effects might be modified in the context of unfolding events. When put in the context of biologic interactions that take place at the tumor site, the Fas/FasL pathway emerges as a molecular mechanism, which contributes to immune privilege and tumor escape, but which can also enhance anti-tumor inflammatory responses. FasL, like many cytokines, is pleiotropic. It is also worth bearing in mind that other molecular players, including the other known members of the TNF family, almost certainly participate in establishing immune privilege status of tumors. While a broad body of new information has contributed to clarifying the dual role of FasL in the tumor biology, much remains to be learned about molecular mechanisms that control its effects in the tumor and in normal tissues.

Apoptosis↗

PubMed2025

T cell subsets of urine-derived lymphocytes (UDLs) serve as an indicator of TILs and reflect immunological sex differences in bladder cancer.

BACKGROUND: Bladder cancer is unique among visceral malignancies in that urine, which can be easily obtained, has prolonged contact with bladder tumors. Urinary biomarkers offer the potential to provide insight into the host and tumor immune microenvironment to guide therapeutic strategies. We evaluated the immune cellular composition of urine (urine-derived lymphocytes (UDLs)) versus tumor (tumor-infiltrating lymphocytes (TILs)). METHODS: We employed high-dimensional flow cytometry analyses on immune cells from tumors (TILs), urine (UDLs), and peripheral blood (peripheral blood mononuclear cells) among patients with bladder cancer. We performed multiplexed immunofluorescence (mIF) of matched tumors to provide spatial context to our findings, comparing deep/invasive and superficial/urine-facing regions of matched tumors. RESULTS: Our findings suggest that the CD4+ and CD8+ T cell subsets of UDLs characterized by flow cytometry had similar phenotypic profiles to those found in TILs (cell clusters quantified by multidimensional scaling and differentiation states). Results of mIF imaging with a panel of phenotypic and functional T cell markers suggested that UDLs reflected TILs in both superficial and deep tumor sections. We also found sex-dependent patterns in TILs and UDLs, indicating the male bladder cancer tumor microenvironment is enriched in exhausted CD4+ and CD8+ T cells, while the female bladder cancer microenvironment is enriched for activated T cells. CONCLUSIONS: Assessment of UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response. UDLs may also reflect sex-based differences in antitumor immunity.

Humans↗

PubMed2001

[Apoptosis and proliferative activity of bone marrow cells in patients with aplastic syndromes as evidenced by trephine biopsy].

AIM: To clarify the effect of cyclosporin A (CSA) on the apoptosis and proliferative activity of bone marrow cells in patients with aplastic syndromes by trepanobiopsy evidence. MATERIALS AND METHODS: The TUNEL immunohistochemical assay was used to study apoptosis of bone marrow cells in the histological specimens from 24 patients: 8 with refractory anemia (RA), 8 with acute small-proportion leukemias [RA with excessive blasts (RAEB) + RAEB in transformation (RAEBt)], 3 with acute non-lymphoblastic leukemia (ANLL), 5 with lymphogranulomatosis (LGM). Control apoptosis examination was made in 10 patients treated with CSA. The proliferative activity of bone marrow cell was evaluated by bone marrow histological specimens from 10 patients (8 patients with RA and 2 with RAEB + RAEBt) at the onset of disease and during CSA therapy in the immunohistochemical test with primary nuclear antigen Ki-67 antigen antibodies. Changes in the proliferative activity and degree of apoptosis of bone marrow cells were assessed in relation to the cellularity detectable by the histological specimens. RESULTS: Patients with RA showed an increase in bone marrow cell apoptosis to 25.375 +/- 6.874 (-10.8 +/- 5.122 and 8.333 +/- 5.84 in controls and ANLL patients, respectively). The cells of hemopoiesis and stromal microenvironment are in the process of cell death. Higher bone marrow cellularity is observed in CSA-treated patients at clinical and hematological remission, which is followed by rises in the index of proliferation and the degree of apoptosis. CONCLUSION: The clinical effect of CSA in patients with aplastic syndromes is induced by its direct or mediated stimulating effect on pluripotent stem cells of hemopoiesis, by increasing bone marrow cellularity at the expense of clonal and/or normal hemopoiesis.

Acute Disease↗

PubMedDate not supplied

Ionizing radiation and leukaemia: more questions than answers.

The mechanisms underlying the unequivocal association between ionizing radiation and the development of leukaemia remain unknown. Recent progress in defining sub-cellular events has contributed to our understanding of the production of genetic lesions in irradiated cells but the importance of tissue effects in response to radiation damage has attracted much less attention. Thus, genetic lesions induced by radiation are considered to result from the deposition of energy in the cell nucleus and the initiating lesion for radiation-induced transformation has been similarly attributed to direct DNA damage. Recently, however, there have been many reports of radiation effects, characteristically associated with the consequences of energy deposition in the cell nucleus, arising in non-irradiated cells as a consequence of communication with irradiated cells. These, so-called, non-targeted radiation effects pose major challenges to current views of the mechanisms of radiation-induced DNA damage and the mechanisms underlying radiogenic malignancies. Considered together with data obtained from laboratory model systems, a rather complex picture of radiation leukaemogenesis is emerging in which, additional to any damage induced directly in target stem cells, the haemopoietic microenvironment can be a source of damaging signals and cellular interactions make important genotype-dependent contributions to determining overall outcome after radiation exposures.

Bystander Effect↗

PubMed1999

Aerotaxis and other energy-sensing behavior in bacteria.

Energy taxis is widespread in motile bacteria and in some species is the only known behavioral response. The bacteria monitor their cellular energy levels and respond to a decrease in energy by swimming to a microenvironment that reenergizes the cells. This is in contrast to classical Escherichia coli chemotaxis in which sensing of stimuli is independent of cellular metabolism. Energy taxis encompasses aerotaxis (taxis to oxygen), phototaxis, redox taxis, taxis to alternative electron acceptors, and chemotaxis to a carbon source. All of these responses share a common signal transduction pathway. An environmental stimulus, such as oxygen concentration or light intensity, modulates the flow of reducing equivalents through the electron transport system. A transducer senses the change in electron transport, or possibly a related parameter such as proton motive force, and initiates a signal that alters the direction of swimming. The Aer and Tsr proteins in E. coli are newly recognized transducers for energy taxis. Aer is homologous to E. coli chemoreceptors but unique in having a PAS domain and a flavin-adenine dinucleotide cofactor that is postulated to interact with a component of the electron transport system. PAS domains are energy-sensing modules that are found in proteins from archaea to humans. Tsr, the serine chemoreceptor, is an independent transducer for energy taxis, but its sensory mechanism is unknown. Energy taxis has a significant ecological role in vertical stratification of microorganisms in microbial mats and water columns. It plays a central role in the behavior of magnetotactic bacteria and also appears to be important in plant-microbe interactions.

Bacterial Physiological Phenomena↗

PubMed2006

The tumour microenvironment and implications for cancer immunotherapy.

Tumour cells exist in a complex milieu of cellular and non-cellular components comprising fibroblasts, endothelial cells, immune cells and metabolites of cellular respiration. An elaborate interplay between these components and tumour cells exists with implications for immunological recognition of tumour cells. Tumours have been shown to alter their antigen and cytokine profiles, desensitise and impair immune defences, signal fibroblasts to facilitate metastasis, and take advantage of acidic and hypoxic conditions that impede normal cells. This paper aims to review the roles of the stroma, extracellular matrix and chemistry of the microenvironment on tumour growth, with particular emphasis on interactions with the immune system, and to highlight some of the novel therapeutic strategies that target the tumour microenvironment.

Antineoplastic Agents↗

PubMed2024

Proteome-Scale Tissue Mapping Using Mass Spectrometry Based on Label-Free and Multiplexed Workflows.

Multiplexed bimolecular profiling of tissue microenvironment, or spatial omics, can provide deep insight into cellular compositions and interactions in healthy and diseased tissues. Proteome-scale tissue mapping, which aims to unbiasedly visualize all the proteins in a whole tissue section or region of interest, has attracted significant interest because it holds great potential to directly reveal diagnostic biomarkers and therapeutic targets. While many approaches are available, however, proteome mapping still exhibits significant technical challenges in both protein coverage and analytical throughput. Since many of these existing challenges are associated with mass spectrometry-based protein identification and quantification, we performed a detailed benchmarking study of three protein quantification methods for spatial proteome mapping, including label-free, TMT-MS2, and TMT-MS3. Our study indicates label-free method provided the deepest coverages of ∼3500 proteins at a spatial resolution of 50 μm and the highest quantification dynamic range, while TMT-MS2 method holds great benefit in mapping throughput at >125 pixels per day. The evaluation also indicates both label-free and TMT-MS2 provides robust protein quantifications in identifying differentially abundant proteins and spatially covariable clusters. In the study of pancreatic islet microenvironment, we demonstrated deep proteome mapping not only enables the identification of protein markers specific to different cell types, but more importantly, it also reveals unknown or hidden protein patterns by spatial coexpression analysis.

Proteome↗

PubMed1994

A novel function for the nm23-H1 gene: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest.

BACKGROUND: We have developed a culture system using reconstituted basement membrane components in which normal human mammary epithelial cells exhibit several aspects of the development and differentiation process, including formation of acinar-like structures, production and basal deposition of basement membrane components, and production and apical secretion of sialomucins. Cell lines and cultures from human breast carcinomas failed to recapitulate this process. The data indicate the importance of cellular interactions with the basement membrane in the regulation of normal breast differentiation and, potentially, its loss in neoplasia. PURPOSE: Our purpose was to use this assay to investigate the role of the putative metastasis suppressor gene nm23-H1 in mammary development and differentiation. METHODS: The metastatic human breast carcinoma cell line MDA-MB-435, clones transfected with a control pCMVBamneo vector, and clones transfected with pCMVBamneo vector containing nm23-H1 complementary DNA (the latter of which exhibited a substantial reduction in spontaneous metastatic potential in vivo) were cultured within a reconstituted basement membrane. Clones were examined for formation of acinus-like spheres, deposition of basement membrane components, production of sialomucin, polarization, and growth arrest. RESULTS: In contrast to the parental cell line and control transfectants, MDA-MB-435 breast carcinoma cells overexpressing Nm23-H1 protein regained several aspects of the normal phenotype within reconstituted basement membrane. Nm23-H1 protein-positive cells formed organized acinus-like spheres, deposited the basement membrane components type IV collagen and, to some extent, laminin to the outside of the spheres, expressed sialomucin, and growth arrested. Growth arrest of Nm23-H1 protein-positive cells was preceded by and correlated with formation of a basement membrane, suggesting a causal relationship. CONCLUSION: The data indicate a previously unidentified cause-and-effect relationship between nm23-H1 gene expression and morphological-biosynthetic-growth aspects of breast differentiation in this model system. IMPLICATIONS: While the basement membrane microenvironment is capable of directing the differentiation of normal human breast cells, neoplastic transformation abrogates this relationship, suggesting that intrinsic cellular events are also critical to this process. The data identify nm23-H1 gene expression as one of these events, suggesting an important role in the modulation of cellular responsiveness to the microenvironment. The data also identify previously unknown growth inhibitory effects of nm23-H1 gene overexpression.

Animals↗

PubMed2024

Proteome-scale tissue mapping using mass spectrometry based on label-free and multiplexed workflows.

Multiplexed bimolecular profiling of tissue microenvironment, or spatial omics, can provide deep insight into cellular compositions and interactions in healthy and diseased tissues. Proteome-scale tissue mapping, which aims to unbiasedly visualize all the proteins in a whole tissue section or region of interest, has attracted significant interest because it holds great potential to directly reveal diagnostic biomarkers and therapeutic targets. While many approaches are available, however, proteome mapping still exhibits significant technical challenges in both protein coverage and analytical throughput. Since many of these existing challenges are associated with mass spectrometry-based protein identification and quantification, we performed a detailed benchmarking study of three protein quantification methods for spatial proteome mapping, including label-free, TMT-MS2, and TMT-MS3. Our study indicates label-free method provided the deepest coverages of ~3500 proteins at a spatial resolution of 50 µm and the highest quantification dynamic range, while TMT-MS2 method holds great benefit in mapping throughput at >125 pixels per day. The evaluation also indicates both label-free and TMT-MS2 provide robust protein quantifications in identifying differentially abundant proteins and spatially co-variable clusters. In the study of pancreatic islet microenvironment, we demonstrated deep proteome mapping not only enables the identification of protein markers specific to different cell types, but more importantly, it also reveals unknown or hidden protein patterns by spatial co-expression analysis.

Journal Article↗

PubMed2001

Chondrocyte deformation within mechanically and enzymatically extracted chondrons compressed in agarose.

Within articular cartilage, the chondron microenvironment will influence chondrocyte behaviour and response to loading. Chondrons were extracted from intact cartilage using either mechanical homogenisation (MC) or enzymatic digestion (EC) and cell and matrix morphology in unstrained and compressed agarose constructs was examined. Isolated chondrocytes (IC) were used for comparison. Immunolocalisation of type VI collagen and keratan sulphate revealed differences in the structure of the pericellular microenvironment such that MC most closely resembled chondrons in situ. The unstrained cell diameters of IC and EC were larger than MC at day 1 and increased significantly over a 7 day culture period. In contrast, cell diameters for MC remained constant. Compression of constructs at day 1 resulted in cell deformation for IC and EC but not MC. The two chondron extraction methods yielded chondrons of differing matrix morphology and associated differences in cell size and cellular response to load. The results indicate that the pericellular microenvironment of MC initially possessed a greater mechanical integrity than that of EC. Although these differences may be reduced with time in culture, characterisation of mechanically isolated chondrons suggests that the stiffness of the chondrons in situ may be greater than previous estimates.

Animals↗

PubMed2006

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Adaptation, Physiological↗

PubMed1993

Organ-specific metastases in immunodeficient mice injected with human melanoma cells: a quantitative pathological analysis.

Pathological and morphometric techniques were used to investigate the potential of two human melanoma cell lines for organ colonization in three different immunodeficient mouse strains; nude (nu/nu), NIH triple immunodeficient (TID: nu/nu, bg/bg, xid/xid) and severe combined immunodeficient (SCID) mice. The MM-RU cell line gave rise exclusively to lung metastases, whereas the MM-AN cell line gave rise to lung and extrapulmonary metastases. Although the TID mice showed more pancreatic and brown fat lesions than nude or SCID mice, the overall pattern of distribution of organ metastases among the strains was similar, suggesting that cellular properties intrinsic to the melanoma cells are important for the colonization of specific organs. The metastatic nodules were well circumscribed in all organs and exhibited peripherally located macrophages, except for brain metastases, where a more invasive pattern along vasculature was observed. The differences in cellular infiltrate and infiltrative patterns of the tumors implicate features of the host microenvironment (organ-specific factors) which are, at least in part, independent of the host's genetic background or degree of immunodeficiency. Our findings suggest that intrinsic malignant cellular properties play an important role in organ-specific colonization by haematogenously metastasizing cells.

Adipose Tissue, Brown↗