A rare tumor of the lung: inflammatory myofibroblastic tumor

ABSTRACT: Inflammatory myofibroblastic tumor is a rare benign lesion whose tumor origin is now proven. It represents 0.7% of all lung tumors. We report the case of a three-year-old child who suffered from a chronic cough with recurrent respiratory infections. Chest X-ray and computed tomography revealed the presence of a left lower lobe lung mass. After pneumonectomy, histological examination combined with immunohistochemical study discovered an inflammatory myofibroblastic tumor. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8722069326962972.     

CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis

Comment on: Capparelli C, et al. Cell Cycle 2012; 11:2272-84 and Capparelli C, et al. Cell Cycle 2012; 11:2285-302.     

Organ-specific pancreatic tumor growth properties and tumor immunity

We established a model of orthotopic injection of a syngeneic pancreatic tumor cell line in C57BL/6 mice and evaluated the effects of organ site on induction of immunity to a tumor-specific antigen, MUC1. Mice were challenged with a syngeneic pancreatic adenocarcinoma cell line that expressed MUC1 (Panc02-MUC1) by orthotopic injection into the pancreas, or by subcutaneous injection. Tumor cells injected into the pancreas grew much faster than those injected subcutaneously. Mice challenged subcutaneously with Panc02-MUC1 rejected tumors or developed slowly growing tumors that were negative for MUC1 expression. In contrast, mice challenged orthotopically into the pancreas developed progressive tumors that were positive for MUC1 expression. Sera from mice that rejected Panc02-MUC1 (tumor-immune mice) showed no detectable IgG1 and IgM titers against the MUC1 tandem-repeat peptide, whereas mice with progressive tumor growth had significant titers of IgG1 and IgM specific for MUC1. This suggests that the humoral immune response was ineffective in mediating tumor rejection. The results show that the growth properties and immunological rejection of pancreatic tumors is affected by the organ site at which the tumor grows. Received: 25 April 1998 / Accepted: 7 October 1998     

Tumor spectrum, tumor latency and tumor incidence of the Pten-deficient mice

Background

Pten functionally acts as a tumor suppressor gene. Lately, tissue-specific ablation of Pten gene in mice has elucidated the role of Pten in different tumor progression models. However, a temporally controlled Pten loss in all adult tissues to examine susceptibility of various tissues to Pten-deficient tumorigenesis has not been addressed yet. Our goal was to explore the genesis of Pten-deficient malignancies in multiple tissue lineages of the adult mouse.

Methods and Findings

We utilized an inducible Cre/loxP system to delete Pten exon 5 in the systemic organs of ROSA26 (R26)-CreER^T;Pten^fx/fx mice. On reaching 45 weeks 4OHT-induced Pten loss, we found that the R26-CreER^T;Pten^fx/fx mice developed a variety of malignancies. Overall tumor mean latency was 17 weeks in the Pten-deficient mice. Interestingly, mutant females developed malignancies more quickly at 10∼11 weeks compared with a tumor latency of 21 weeks for mutant males. Lymphoma incidence (76.9% in females; 40.0% in males) was higher than the other malignancies found in the mutant mice. Mutant males developed prostate (20.0%), intestinal cancer (35.0%) and squamous cell carcinoma (10.0%), whereas the mutant females developed squamous cell carcinoma (15.4%) and endometrial cancer (46.1%) in addition to lymphomas. Furthermore, we tested the pharmacological inhibition of the PTEN downstream effectors using {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 on Pten-deficient prostate hyperplasia. Our data revealed that, indeed, the prostate hyperplasia resulting from the induced Pten loss was significantly suppressed by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 (p = 0.007).

Conclusions

Through monitoring a variety of Pten-deficient tumor formation, our results revealed that the lymphoid lineages and the epithelium of the prostate, endometrium, intestine and epidermis are highly susceptible to tumorigenesis after the Pten gene is excised. Therefore, this R26-CreER^T; Pten^fx/fx mouse model may provide an entry point for understanding the role of Pten in the tumorigenesis of different organs and extend the search for potential therapeutic approaches to prevent Pten-deficient malignancies.     

Prostaglandins and cancer: A review of tumor initiation through tumor metastasis

Prostaglandin is a term applied to a series of compounds derived enzymatically and nonenzymatically from 20 carbon fatty acids such as arachidonic acid (20:4). Research over the past 20 years has identified the prostaglandins as products of almost every cell although the amount and class of prostaglandin produced varies considerably with cell type. Within the last ten years additional, related products of 20:4 metabolism (operationally termed eicosanoids) have been discovered, eg. prostacyclin, thromboxanes, malondialdehyde, leukotrienes, hydroperoxy and hydroxy fatty acids. The role of these 20:4 metabolites in physiological and pathological states is currently under intensive investigation and the biological action of these compounds have been implicated in many key regulatory processes. Therefore, it is not unreasonable to predict that these potent bioregulatory compounds may have a central role in the initiation and regulation (positive and negative) of the spectrum of diseases which we functionally term “cancer”.     

Reconstructing tumor amplisomes

MOTIVATION: Duplication of genomic sequences is a common phenomenon in tumor cells. While many duplications associated with tumors have been identified (e.g. via techniques such as CGH), both the organization of the duplicated sequences and the process that leads to these duplications are less clear. One mechanism that has been observed to lead to duplication is the extraction of DNA from the chromosomes and aggregation of this DNA into small, independently replicating linear or circular DNA sequences (amplisomes). Parts of these amplisomes may later be reinserted back into the main chromosomes leading to duplication. Although amplisomes are known to play an important role in tumorigenesis, their architecture and even size remain largely unknown. RESULTS: We reconstruct the structure of tumor amplisomes by analyzing duplications in the tumor genome. Our approach relies on recently generated data from End Sequence Profiling (ESP) experiments, which allow us to examine the fine structure of duplications in a tumor on a genome-wide scale. Using ESP data, we formulate the Amplisome Reconstruction Problem, describe an algorithm for its solution, and derive a putative architecture of a tumor amplisome that is the source for duplicated material in the MCF7 breast tumor cell line.     

Metabolism shapes the tumor microenvironment

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The age-related tumor incidence in Wistar-Imamichi rat

The age-related incidences and types of spontaneous tumors were studied in 320 male and 354 female Wistar-Imamichi rats reared up to 130 weeks of age. The tumor incidence increased abruptly between 53 and 78 weeks of age, and 170 males and 269 females were shown to bear tumors during the observation period. Multiple tumors occurred in 62 males and 115 females. Most common were hypophyseal (male 69: female 224), mammary gland (29:99), testicular (74:0) and adrenal gland (26:21) tumors. The incidences of hypophyseal and testicular tumors increased with age. Tumors occurred in later stages of the observation period in the ovary, uterus and vagina (0:27), thyroid and parathyroid (13:12), skin (8:8), spleen and lymph nodes (8:7), pancreas (9:5), liver (3:7), lung (3:3), thymus (1:4), omentum and mesenterium (2:3), stomach and intestine (2:2), kidney and urinary bladder (1:2), right femur (0:1), and brain (0:1).     

Nonlinear simulation of tumor growth

 We study solid tumor (carcinoma) growth in the nonlinear regime using boundary-integral simulations. The tumor core is nonnecrotic and no inhibitor chemical species are present. A new formulation of the classical models [18,24,8,3] is developed and it is demonstrated that tumor evolution is described by a reduced set of two dimensionless parameters and is qualitatively unaffected by the number of spatial dimensions. One parameter describes the relative rate of mitosis to the relaxation mechanisms (cell mobility and cell-to-cell adhesion). The other describes the balance between apoptosis (programmed cell-death) and mitosis. Both parameters also include the effect of vascularization. Our analysis and nonlinear simulations reveal that the two new dimensionless groups uniquely subdivide tumor growth into three regimes associated with increasing degrees of vascularization: low (diffusion dominated, e.g., in vitro), moderate and high vascularization, that correspond to the regimes observed in vivo. We demonstrate that critical conditions exist for which the tumor evolves to nontrivial dormant states or grows self-similarly (i.e., shape invariant) in the first two regimes. This leads to the possibility of shape control and of controlling the release of tumor angiogenic factors by restricting the tumor volume-to-surface-area ratio. Away from these critical conditions, evolution may be unstable leading to invasive fingering into the external tissues and to topological transitions such as tumor breakup and reconnection. Interestingly we find that for highly vascularized tumors, while they grow unbounded, their shape always stays compact and invasive fingering does not occur. This is in agreement with recent experimental observations [30] of in vivo tumor growth, and suggests that the invasive growth of highly-vascularized tumors is associated to vascular and elastic anisotropies, which are not included in the model studied here. Received: 1 May 2002 / Revised version: 26 August 2002 / Published online: 18 December 2002 Current address: Department of Biomedical Engineering, and Department of Mathematics, University of California at Irvine, Irvine CA 92697. e-mail: cristini@math.uci.edu; lowengrb@math.umn.edu. Key words or phrases: Tumor growth – Linear stability analysis – Self-similarity – Boundary-integral simulations     

Polyploid mitosis and depolyploidization promote chromosomal instability and tumor progression in a Notch-induced tumor model

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Three-dimensional imaging of tumor angiogenesis

OBJECTIVE: To three-dimensionally visualize the microvessel environment of tumor angiogenesis by confocal laser scanning microscopy (CLSM). STUDY DESIGN: To reveal underlying mechanisms of tumor angiogenesis, a 7, 12-dimethylbenz(a) anthracene-induced rat cancer model was used. For demonstrating tumor vasculature, fluorescence injection method (FITC-conjugated gelatin solution) was employed. FITC gelatin was injected into the left ventricle of the rat heart. After complete perfusion, the mammary glands were resected, fixed under ice cold conditions and subjected to immunohistochemistry (IHC) for tumor cells. The LSM-410 (Carl Zeiss, Jena, Germany) was employed on thick sections (300-2,000 microns) to elucidate detailed microvessel networks (MVN) and tumor cells. RESULTS: Tumor vasculature on thick sections was clearly detected by CLSM at the maximum focus depth of 2,000 microns. Three-dimensional (3-D), reconstructed images of normal mammary glands showed regular and linear MVN. In DMBA-induced mammary cancer, vascular density of MVN was markedly increased and showed an anastomosing, irregular MVN pattern. Furthermore, focal segmentation and tortuous, branching patterns of microvessels were also seen. CONCLUSION: Application of the fluorescence injection method and IHC using CLSM was very useful for studying the 3-D relationship between tumor angiogenesis and neoplastic epithelial changes. These results suggest that application of this technique is ideal for studying 3-D imaging of tumor angiogenesis.     

Cytopathology of oncocytic carcinoid tumor of the lung mimicking granular cell tumor. A case report

BACKGROUND: The cytopathologic features of oncocytic carcinoid tumor of the lung, a rare variant of carcinoid tumor that is composed exclusively of oncocytes, have not been described before in detail. CASE: The bronchial brush smears from an 80-year-old female with an endobronchial obstructive tumor showed single and loose clusters of tumor cells with abundant granular, eosinophilic cytoplasm. The differential diagnoses included oncocytic carcinoid tumor, granular cell tumor, other oncocytic tumors of bronchial origin and metastatic oncocytic tumors. Immunocytochemistry and electron microscopy confirmed the diagnosis of oncocytic carcinoid tumor. CONCLUSION: Oncocytic carcinoid tumor of the lung has cytopathologic features similar to those of granular cell tumor and pulmonary oncocytoma. Immunocytochemistry, electron microscope or both are necessary to distinguish these neoplasms.     

New role for Spinophilin in tumor suppression

Comment on: Ferrer I, et al. Cell Cycle 2011; 10:2751-62.     

A late recurring and easily forgotten tumor: ovarian granulosa cell tumor

ABSTRACT: Ovarian granulosa cell tumor (GCT) is a malignant tumor with slow progression. The recurrence of granulosa cell tumor often happens after 5 years, leading to a 'forgotten tumor' by the patient. We present the case of a 64-year-old woman with a presentation of left flank pain. An initial computed tomography scan revealed a single tumor with multiple adjacent organ invasions. Surgical intervention was prescribed and the pathological results revealed a metastatic granulosa cell tumor. We also review the literature for the follow-up and further management of this tumor.     

RANK links senescence to stemness in the mammary epithelia,delaying tumor onset but increasing tumor aggressiveness

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Intra-abdominal desmoplastic small round cell tumor

BACKGROUND: Intra-abdominal desmoplastic small round cell tumor is a rare malignancy with a predilection for young males. Unique histological and immunocytochemical features distinguish the tumor from other members of the family of small round cell tumors of infancy and childhood. The aggressive nature of tumor spread, relative insensitivity to chemotherapy, and generally incomplete resectability result in a very poor prognosis. The authors report a case of a 39-year-old man with diffuse abdominal and pelvic involvement of intra-abdominal desmoplastic small round cell tumor treated with aggressive chemotherapy and surgery. METHODS: Computed tomography (CT)-guided biopsy of an omental mass was performed. Histologically, discrete nests of uniform closely packed malignant cells were distributed in a background of focally desmoplastic stroma. Immunocytochemistry demonstrated positivity for epithelial, mesenchymal, and neural markers. On the basis of these unique histological and immunohistochemical characteristics, the diagnosis of desmoplastic small round cell tumor was made. The patient was treated with aggressive neoadjuvant chemotherapy consisting of a high-dose alkylator -based combination regimen, followed by surgery. RESULTS: The patient had a 10 to 15 percent regression in tumor mass in response to chemotherapy. Laparotomy revealed two large omental masses, another large mass adherent to the left colon and pelvic sidewall, and diaphragmatic, peritoneal and mesenteric studding with small nodules. Complete surgical resection was not possible. CONCLUSIONS: Intra-abdominal desmoplastic small round cell tumor remains an aggressive malignancy with an extremely poor prognosis. Although some response to chemotherapy may be possible, complete resection is rare, and surgical efforts are generally palliative.     

Intra-abdominal desmoplastic small round cell tumor

BACKGROUND: Intra-abdominal desmoplastic small round cell tumor is a rare malignancy with a predilection for young males. Unique histological and immunocytochemical features distinguish the tumor from other members of the family of small round cell tumors of infancy and childhood. The aggressive nature of tumor spread, relative insensitivity to chemotherapy, and generally incomplete resectability result in a very poor prognosis. The authors report a case of a 39-year-old man with diffuse abdominal and pelvic involvement of intra-abdominal desmoplastic small round cell tumor treated with aggressive chemotherapy and surgery. METHODS: Computed-tomography (CT)-guided biopsy of an omental mass was performed. Histologically, discrete nests of uniform closely packed malignant cells were distributed in a background of focally desmoplastic stroma. Immunocchemistry demonstrated positivity for epithelial, mesenchymal, and neural markers. On the basis of these unique histological and immunohistochemical characteristics, the diagnosis of desmoplastic small round cell tumor was made. The patient was treated with aggressive neoadjuvant chemotherapy consisting of a high-dose alkylator -based combination regimen, followed by surgery. RESULTS: The patient had a 10 to 15 percent regression in tumor mass in response to chemotherapy. Laparotomy revealed two large omental masses, another large mass adherent to the left colon and pelvic sidewall, and diaphragmatic, peritoneal and mesenteric studding with small nodules. Complete surgical resection was not possible. CONCLUSIONS: Intra-abdominal desmoplastic small round cell tumor remains an aggressive malignancy with an extremely poor prognosis. Although some response to chemotherapy may be possible, complete resection is rare, and surgical efforts are general palliative.     

Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance

ABSTRACT: Activation of oncogenes is generally associated with the induction of DNA damage response (DDR) signaling, which acts as a barrier to tumor progression. In this review we will present an overview of the DDR associated with oncogenic activation of Myc, with special focus on two opposite and paradoxical aspects of this response: (1) the role of the Myc-induced DDR in tumor suppression; (2) its role in dampening Myc-induced replication stress, thereby protecting the viability of prospective cancer cells. These opposing effects on cancer progression are controlled by two different branches of DDR signaling, respectively ATM/CHK2 and ATR/CHK1. Indeed, while ATM activity constitutes a barrier to malignant transformation, full activation of ATR and CHK1 is essential for tumor maintenance, providing important opportunities for therapeutic intervention. Thus, the Myc-induced DDR acts as a double-edged sword in tumor progression.     

Dendritic cells presenting tumor antigen

 Since the first identification of dendritic cells by Steinman and Cohn in 1973, progress in understanding their biology has included the development of novel methods of cell culture, recognition of critical aspects of migration and maturation, and appreciation of their major role as antigen-presenting cells (APC), and how this activity is regulated by cytokines and expression of accessory molecules. Dendritic cells are the major APC involved in the initiation of the immune response and the development of tolerance. There is considerable evidence that they can acquire antigen in the peripheral tissues and process, transport, and present it to T cells in secondary lymphoid tissue. A number of studies show that, in vitro or in vivo, antigen-pulsed dendritic cells can directly sensitize T cells and stimulate the development of antigen-specific immune responses, including both protective and therapeutic antitumor responses. In this paper, several important aspects of dendritic cell biology are discussed and a number of studies confirming the role of these professional APC in antitumor immunity are reviewed. Received: 6 August 1996 / Accepted: 20 September 1996     

TARC and RANTES enhance antitumor immunity induced by the GM-CSF-transduced tumor vaccine in a mouse tumor model

INTRODUCTION: Transduction of the granulocyte-macrophage colony stimulating factor (GM-CSF) gene into mouse tumor cells abrogates their tumorigenicity in vivo. Our previous report demonstrated that gene transduction of GM-CSF with either TARC or RANTES chemokines suppressed in vivo tumor formation. In this paper, we examined whether the addition of either recombinant TARC or RANTES proteins to irradiated GM-CSF-transduced tumor vaccine cells enhanced antitumor immunity against established mouse tumor models to examine its future clinical application. MATERIALS AND METHODS: Three million irradiated WEHI3B cells retrovirally transduced with murine GM-CSF cDNA in combination with either recombinant TARC or RANTES were subcutaneously inoculated into syngeneic WEHI3B-preestablished BALB/c mice. RESULTS: Vaccinations were well tolerated. Mice treated with GM-CSF-transduced cells and the chemokines demonstrated significantly longer survival than mice treated with GM-CSF-transduced cells alone. Splenocytes harvested from mice treated with the former vaccines produced higher levels of IL-4, IL-6, IFN-gamma, and TNF-alpha, suggesting enhanced innate and adaptive immunity. Immunohistochemical analysis of tumor sections after vaccination revealed a more significant contribution of CD4+ and CD8+ T cells to tumor repression in the combined vaccine groups than controls. CONCLUSIONS: TARC and RANTES enhance the immunological antitumor effect induced by GM-CSF in mouse WEHI3B tumor models and may be clinically useful.