Tumor counterattack: fact or fiction?

Cancer development relies on a variety of mechanisms that facilitate tumor growth despite the presence of a functioning immune system. Understanding these mechanisms may foster novel therapeutic approaches for oncology and organ transplantation. By expression of the apoptosis-inducing protein CD95L (FasL, APO-1L, CD178), tumors may eliminate tumor-infiltrating lymphocytes and suppress anti-tumor immune responses, a phenomenon called tumor counterattack. On the one hand, preliminary evidence of tumor counterattack in human tumors exists, and CD95L expression can prevent T-cell responses in vitro. On the other hand, CD95L-expressing tumors are rapidly rejected and induce inflammation in mice. Here, we summarize and discuss the consequences of CD95L expression of tumor cells and its contribution to immune escape.This article is a symposium paper from the conference Tumor Escape and Its Determinants, held in Salzburg, Austria, on 10–13 October 2004.     

A Validated Mathematical Model of Tumor Growth Including Tumor–Host Interaction,Cell-Mediated Immune Response and Chemotherapy

We consider a dynamical model of cancer growth including three interacting cell populations of tumor cells, healthy host cells and immune effector cells. The tumor–immune and the tumor–host interactions are characterized to reproduce experimental results. A thorough dynamical analysis of the model is carried out, showing its capability to explain theoretical and empirical knowledge about tumor development. A chemotherapy treatment reproducing different experiments is also introduced. We believe that this simple model can serve as a foundation for the development of more complicated and specific cancer models.     

Tumor microenvironment–associated modifications of alternative splicing

Pre-mRNA alternative splicing is modified in cancer, but the origin and specificity of these changes remain unclear. Here, we probed ovarian tumors to identify cancer-associated splicing isoforms and define the mechanism by which splicing is modified in cancer cells. Using high-throughput quantitative PCR, we monitored the expression of splice variants in laser-dissected tissues from ovarian tumors. Surprisingly, changes in alternative splicing were not limited to the tumor tissues but were also found in the tumor microenvironment. Changes in the tumor-associated splicing events were found to be regulated by splicing factors that are differentially expressed in cancer tissues. Overall, ∼20% of the alternative splicing events affected by the down-regulation of the splicing factors QKI and RBFOX2 were altered in the microenvironment of ovarian tumors. Together, our results indicate that the tumor microenvironment undergoes specific changes in alternative splicing orchestrated by a limited number of splicing factors.     

Does Caspase Inhibition Promote Clonogenic Tumor Growth?

Defects in the control of cell death are a major cause of resistance to tumor therapy. Until recently, components of the intrinsic apoptotic pathway that act downstream of mitochondria, such as the caspases, have been apportioned only a minor share in this business. Thus, defects in mitochondrial caspase activation were suggested to cause apoptosis inhibition but not to confer clonogenic survival. This assumption was based on the finding that chemotherapeutic agents provoke mitochondrial damage even the absence of caspases, resulting in the release various toxic mediators and a subsequent caspase-independent cell death. In contrast to these earlier observations, we recently showed that in the absence of active caspases tumor cells do not necessarily undergo caspase-independent cell death but may even survive a chemotherapeutic insult. Our findings suggest that caspase inhibition can indeed promote clonogenic tumor growth which might be not only relevant for tumor therapy but should be also considered when evaluating the safety of therapeutic caspases inhibitors.     

Is Ewing's Sarcoma a Stem Cell Tumor?

Solving the histogenesis of Ewing's sarcoma has defied investigators despite progress in understanding its molecular pathogenesis. In a recent issue of Cancer Cell, Tirode et al. (2007) present evidence supporting the hypothesis that this rare cancer arises from a primitive mesenchymal precursor.     

Clones of Tumor Cells Derived from a Single Primary Human Lung Tumor Reveal Different Patterns of β1 Integrin Expression

Previously we reported that over 75% of human non-small cell lung cancers overexpress the βi integrin VLA-2 on their surface and show an increase in the mRNA encoding the α-2 chain of this integrin. These results suggested the possibility that the overproduction and overexpression of one or more of the β₁ integrin may be involved in the pathogenesis of human lung tumors by modulating the invasive and/or metastatic potential of the tumor. We report here the generation and characterization of multiple clones of tumor cells derived from the primary culture of cells obtained from biopsy tissue of an aggressive human squamous cell lung tumor. We show that these tumor clones (or clonotypes) exhibit seven different yet stable phenotypes with respect to the expression of five members of the βi integrin family. These results illustrate that a primary human lung tumor consists of multiple subpopulations of cells that while indistinguishable by ultrastructure are heterogeneous with respect to their β₁ integrins. The availability of these distinct tumor clonotypes derived from a single tumor biopsy have made it possible to test the assumption that the βi integrins play a role in tumor progression. The feasibility of this approach is demonstrated here by the intravenous inoculation of different human tumor clonotypes into severe combined immunodeficient (scid) mice. Our preliminary results with a pair of tumor clonotypes differing in VLA-1 and VLA-2 expression level reveal that the clonotype with high level of VLA-1 and VLA-2 displays a substantial increase in the experimental engraftment and metastasis of the human tumor cells in scid mice.     

Tumor Necrosis Factor α Reduces SNAP29 Dependent Autolysosome Formation to Increase Prion Protein Level and Promote Tumor Cell Migration

Virologica Sinica - Tumor Necrosis Factor α (TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of...     

Νον-Islet Cell Tumor Hypoglycemia Associated With Uterine Leiomyomata

ObjectiveWe report a case of non-islet cell tumor hypoglycemia (NICTH) in a patient with large leiomyomata.MethodsWe present the clinical, laboratory, and pathologic findings of a diabetic patient who presented with recurrent hypoglycemia later linked to uterine leiomyomata.ResultsAn 80-year-old woman with diabetes was admitted after falling at home. She reported dizziness and had recorded low capillary blood glucose despite discontinuing her diabetic medication prior to admission. Her physical examination was remarkable for nonorthostatic vital signs, normal cardiovascular and lung examination, and a pelvi-abdominal mass the size of a gravid uterus at 28 weeks of gestation. After receiving a 50% dextrose infusion, she became alert with no focal neurological deficit. Capillary blood glucose rose from 31 mg/ dL to 110 mg/dL. A pelvic sonogram confirmed fibromyomata. She was initially treated with steroids after ahormonal profile suggested NICTH (normal fasting insulin, C-peptide, cosyntropin and glucagon stimulation tests, and negative insulin antibodies). Insulinlike growth factor (IGF) levels were IGF-1, 69 ng/mL and IGF-2, 782 ng/mL, and the IGF-2/IGF-1 ratio was 10.8. The patient underwent a total abdominal hysterectomy. Pathology reported a 3-kg uterus with multiple, large cellular fibromyomas. After steroids were discontinued, she became hyperglycemic requiring insulin and oral diabetic agents. Repeat IGF-2 and IGF-1 measurements were 261 ng/mL and 36 ng/mL, respectively. She was discharged 2 weeks after surgery.ConclusionNICTH is a rare complication associated with large neoplasms. Leiomyomata should be included in the differential diagnoses of NICTH. Surgery is curative in such cases. (Endocr Pract. 2011;17:e109-e112)     

Tumor microenvironment – Unknown niche with powerful therapeutic potential

Head and neck squamous cell carcinomas (HNSCC) are in a group of cancers that are the most resistant to treatment. The survival rate of HNSCC patients has been still very low since last 20 years. The existence of relationship between oncogenic and surrounding cells is probably the reason for a poor response to treatment. Fibroblasts are an important element of tumor stroma which increases tumor cells ability to proliferate. Another highly resistance, tumorigenic and metastatic cell population in tumor microenvironment are cancer initiating cells (CICs). The population of cancer initiating cells can be found regardless of differentiation status of cancer and they seem to be crucial for HNSCC development.In this review, we describe the current state of knowledge about HNSCC biological and physiological tumor microenvironment.     

Tumor necrosis factor α knockout increases fertility of mice

Tumor necrosis factor α (TNFα) acts through two receptors, TNFα receptor| (TNFR|) and TNFα‖ (TNFR‖). Tumor necrosis factor α receptor| knockout mice had early senescence and poor fertility, whereas TNFR‖ knockout mice had reproductive performance not different from wild type (WT) mice. In the present study, TNFα knockout mice were used to study the roles of TNFα in female reproduction. The TNFα−/− mice had similar vaginal opening time (PD 27.6 ± 1.8 vs PD 27.7 ± 1.9, respectively, P > 0.05) and exogenous gonadotropin primed TNFα−/− mice shed more ova (28.9 ± 3.75 vs 9.8 ± 0.51, respectively, P = 0.001) compared with WT controls. At 2 mo of age, in 21 d, TNFα−/− mice had more estrous cycles than WT counterparts (6.0 ± 0.25 vs 4.0 ± 0.28, respectively, P < 0.05). Tumor necrosis factor α mutation also influenced ovarian follicular development; TNFα−/− mice had approximately a two-fold larger follicle pool in the early neonatal period (6087 ± 508.15 vs 3440 ± 261.91, respectively, P = 0.004), whereas TNFα knockout affected growth of primordial follicles to the antral stage as well. Moreover, TNFα−/− mice gave birth to 21% more pups than control mice during a 12 mo breeding period (37.38 ± 3.69 vs 22.38 ± 3.53, respectively, P = 0.03). At 1 y of age, the follicular reserve in TNFα−/− mice was more than that in WT mice. These physiological differences in TNFα−/− mice were associated with increased proliferation of granulosa cells and decreased apoptosis of oocytes. This was apparently the first demonstration that in the TNFα−/− mouse model, multiple parameters of ovarian function were altered, and that lack of TNFα increased fertility in mice.     

Suppression of Tumor Angiogenesis by G��13 Haploinsufficiency

Heterotrimeric G proteins are critical transducers of cellular signaling. Of the four families of G proteins, the physiological function of Gα₁₃ is less well understood. Gα₁₃ gene-deleted mice die at embryonic day ∼9.5. Here, we show that heterozygous Gα₁₃^+/− mice display defects in adult angiogenesis. Female Gα₁₃^+/− mice showed a higher number of immature follicles and a lower density of blood vessels in the mature corpus luteum compared with Gα₁₃^+/+ mice. Furthermore, implanted tumors grew slower in Gα₁₃^+/− host mice. These tumor tissues had many fewer blood vessels compared with those from Gα₁₃^+/+ host mice. Moreover, bone marrow-derived progenitor cells from Gα₁₃^+/+ mice rescued the failed growth of allografted tumors when reconstituted into irradiated Gα₁₃^+/− mice. Hence, Gα₁₃ is haploinsufficient for adult angiogenesis in both the female reproductive system and tumor angiogenesis.A structurally diverse repertoire of ligands, from photons to large peptides, activates G protein-coupled receptors to elicit their physiological functions (1). In turn, ligand-bound G protein-coupled receptors function as guanine nucleotide exchange factors, catalyzing the exchange of GDP bound on the Gα subunit with GTP in the presence of Gβγ and causing the dissociation of the Gα subunit from the Gβγ dimer to form two functional units (Gα and Gβγ) (2). Both Gα and Gβγ subunits signal to various cellular pathways. Based on sequence and functional homologies, G proteins are grouped into four families: G_s, G_i, G_q, and G₁₂ (3). Of these four subfamilies of G proteins, the physiological function of the G₁₂ subfamily is less well understood. In this family, there are two members, G₁₂ and G₁₃. Gα₁₂ knock-out mice appear normal (4). Gα₁₃ knock-out mice display embryonic lethality (embryonic day ∼9.5) (5). Gα₁₃^−/− mouse embryos have defective vascular systems (5). Endothelial cell-specific deletion of Gα₁₃ also results in vascular defect and embryonic lethality (6). The molecular basis that underlies the vascular defect observed in Gα₁₃^−/− mouse embryos has not been defined.Angiogenesis (formation of endothelium-lined blood vessels) is essential for organ growth in the embryo and for repair of wounded tissues in the adult (7, 8). An imbalance in angiogenesis contributes to the pathogenesis of numerous malignant, inflammatory, ischemic, infectious, and immune disorders and cancers (7, 8). Most angiogenesis events take place during embryonic development. In adult tissues, the majority of endothelial cells are quiescent, and angiogenesis occurs only rarely except in a few adult tissues (including ovary) that exhibit periodic and dynamic growth and regression (9–11). Under pathological conditions such as tumor growth, adult angiogenesis is induced. Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths (including implanted tumor tissues), supplying nutrients and oxygen and removing waste products. Solid tumors depend on angiogenesis for growth and metastasis in a hostile environment (12). Bone marrow is the origin of endothelial progenitor cells in the adult. Bone marrow-derived endothelial progenitor cells are mobilized into peripheral blood and recruited to the foci of pathophysiological neovascularization and re-endothelialization, thereby contributing to vascular regeneration (13). Vascular endothelial growth factor (VEGF),² the most critical factor for angiogenesis, is an important factor for the mobilization of endothelial progenitor cells from bone marrow (7, 8). Bone marrow transplantation experiments have demonstrated the incorporation of bone marrow-derived endothelial progenitor cells into foci of pathological neovascularization such as growing tumors, healing wounds, ischemic skeletal and cardiac muscles, and cornea receiving micropocket surgery (14–21).Here, we show that heterozygous Gα₁₃^+/− mice display defects in adult angiogenesis. We found that female Gα₁₃^+/− mice show a higher number of immature follicles and a lower density of blood vessels in the mature corpus luteum compared with Gα₁₃^+/+ mice. Furthermore, implanted tumors grew slower in Gα₁₃^+/− host mice. These tumor tissues had many fewer blood vessels compared with those from Gα₁₃^+/+ host mice. We also down-regulated Gα₁₃ in endothelial cells by RNA interference and show that defective migration and tube formation in response to VEGF likely contribute to the impaired angiogenesis. Moreover, bone marrow-derived cells from Gα₁₃^+/+ mice rescued the failed growth of allografted tumors when reconstituted into irradiated Gα₁₃^+/− mice. Our results demonstrate that Gα₁₃ is haploinsufficient for adult angiogenesis in both the female reproductive system and tumor angiogenesis. This role in adult angiogenesis provides a suitable system to further investigate the biochemical and physiological functions of Gα₁₃. Moreover, Gα₁₃ inhibition could be explored for anticancer drug development.     

Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting

1. Download high-res image (243KB)
2. Download full-size image