Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base

Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

Purpose: Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors. Patients and Methods: We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum. Results: We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10-4), TGFBR1*6A (p = 1.6 × 10-4) and rs11568785 (p = 1.4 × 10-4). Conclusion: These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies

TGF-β in progression of liver disease

Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time

Role of Cancer Microenvironment in Metastasis: Focus on Colon Cancer

One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model

Fragility Analysis of Coastal Roadways and Performance Assessment of Coastal Transportation Systems Subjected to Storm Hazards

Coastal transportation systems are extremely vulnerable due to the coupled impacts of storm surge, waves, and inundation. Existing literature has developed coastal fragility models for bridges. However, to date, flood fragility models for coastal roadways are lacking. For this purpose, the current study proposes a data-driven fragility model based on logistic regression for coastal roadways, with failure probability conditioned on distance to shoreline and inundation duration, using hindcast data for Hurricane Ike. In addition, the effect of bridge and roadway damage on transportation network performance is investigated through a case study on Galveston Island, Texas. The results indicate the spatial distribution of storm impacts on the transportation network, with select roads highly vulnerable if they are located within a couple of hundred meters of the shoreline. In addition, considering roadway damage in addition to bridge damage alone, which is the current state of the art, can have a significant impact on decreasing the performance of the transportation network. Such analyses shed light on potential policy or risk mitigation practices that are expected to be increasingly important in the future as sea level rise further reduces roadway distance to the shoreline or as storm intensity and frequency changes

Abstract 916A: Cancer cell proliferation is inhibited by specific modulation frequencies

Abstract Background: Hepatocellular carcinoma (HCC), a leading cause of cancer death worldwide, now has the fastest growing rate in the United States. The intrabuccal administration of amplitude modulated electromagnetic fields (AM-EMF) is a novel, minimally invasive treatment modality. There is clinical evidence that this novel treatment approach elicits therapeutic responses in patients with cancer (1, 2). However, there is no known mechanism explaining the anti-proliferative effect of very low intensity electromagnetic fields. Methods: Hepatocellular carcinoma cells were exposed to 27.12 MHz radiofrequency electromagnetic fields using in vitro exposure systems designed to replicate in vivo conditions. Cancer cells were exposed to tumor-specific modulation frequencies, previously identified by biofeedback methods in patients with a diagnosis of cancer. Control modulation frequencies consisted of randomly-chosen modulation frequencies within the same 100 Hz to 21 kHz range as cancer-specific frequencies. Growth inhibition was evaluated by measuring tritiated thymidine incorporation. RNA-Seq was used to identify genes with differential expression in cells exposed to HCC-specific AM-EMF. Confocal laser scanning microscopy allowed the visualization of the mitotic spindle. Karyotype assessment compared HepG2 receiving HCC-specific AM-EMF to those not receiving exposure. Results: The growth of hepatocellular carcinoma and breast cancer cells was significantly decreased by hepatocellular carcinoma-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of hepatocellular carcinoma cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, hepatocellular carcinoma-specific modulation frequencies disrupted the mitotic spindle. Karyotype analysis was unrevealing. Conclusion: These findings uncover a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology. Reference List (1) Barbault A, Costa F, Bottger B, Munden R, Bomholt F, Kuster N, et al. Amplitude-modulated electromagnetic fields for the treatment of cancer: Discovery of tumor-specific frequencies and assessment of a novel therapeutic approach. Journal of Experimental &amp; Clinical Cancer Research 2009;28:51. (2) Costa FP, de Oliveira AC, Meirelles R, Machado MCC, Zanesco T, Surjan R, et al. Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields. Br J Cancer 2011;105:640-8. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 916A. doi:1538-7445.AM2012-916A</jats:p

Abstract 1406: Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk.

Abstract Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk and has impaired TGF-β signaling capability. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of several types of cancer, including breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). To investigate the effects of constitutively decreased TGFBR1 signaling on cancer development, we developed a novel mouse model of Tgfbr1 haploinsufficiency to mimic the decreased TGFBR1 signaling observed in individuals with higher risk of cancer. Using this model, we demonstrated that Apcmin;Tgfbr1+/- mice develop more than twice as many intestinal tumors as Apcmin controls. The aim of the current study was to assess the effects of Tgfbr1 haploinsufficiency on breast carcinogenesis by crossing Tgfbr1+/- mice with the MMTV-c-Neu mouse model. Methods: Fully congenic (100%) FVB/N-Tgfbr1+/- mice were crossed with FVB/N-Neu mice, and female virgin progeny were kept for analysis. Mammary glands were collected from 10, 12, and 40 week-old Neu and Neu;Tgfbr1+/- mice. Mice assessed for tumor development were sacrificed 80 days after the initial tumor palpation or at the earliest sign of morbidity. Whole lungs, tumor tissue, and primary tumor cells were collected for additional analysis. Long-term evaluation of 2-year-old Tgfbr1+/+ and Tgfbr1+/- mice was also conducted to directly assess the impact of Tgfbr1 haploinsufficiency on mammary gland and lung development. Results: Mammary gland whole mounts revealed that Neu;Tgfbr1+/- mice have more ductal branching at all time points compared to Neu mice. In the assessment of breast tumor development, Neu;Tgfbr1+/- mice were observed to have a significantly shorter tumor latency period (171 days) compared to Neu mice (220 days) (p=0.004). Seventy percent of Neu;Tgfbr1+/- mice (14/20) developed surface lung metastases, while 36.4% were observed in Neu mice (8/22), a borderline significant difference (p=0.061). The TGF-β-mediated growth inhibition of Neu;Tgfbr1+/- primary tumor cells was 32.2% lower than that of Neu tumor cells (p=0.007). Neu;Tgfbr1+/- tumor cells and tissue had significantly reduced Smad2/3 phosphorylation and total Cdkn1b (p27Kip1) expression compared to Neu mice. Long-term evaluation of Tgfbr1+/- and wild-type mice revealed no signs of mammary gland hyperplasia or differences in lung fibrosis in either group. Conclusion: This study is the first in vivo evidence that Tgfbr1 haploinsufficiency promotes breast carcinogenesis by increasing breast cancer proliferation. The relevance of this data to human breast cancer warrants additional investigations into the effects of decreased TGFBR1 signaling on tumor development and progression and identifies potential targets for prevention and treatment. Citation Format: Michael J. Pennison, Diana S. Rosman-Balzer, Lakisha Moore-Smith, Jacquelyn W. Zimmerman, Trenton R. Schoeb, Andra R. Frost, Ming Zhang, Peter M. Siegel, Boris C. Pasche. Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1406. doi:10.1158/1538-7445.AM2013-1406 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.</jats:p

Abstract 5612: Cancer cell proliferation is inhibited by specific modulation frequencies.

Abstract Purpose: Hepatocellular carcinoma (HCC) incidence in the US is dramatically increasing. Five-year survival remains 3-5%, demonstrating urgent need for additional therapies. Intrabuccal administration of amplitude modulated electromagnetic fields (RF EMF) is a novel, minimally invasive treatment modality which results in whole body absorption of very low levels of RF EMF. Clinical studies show that this treatment approach elicits therapeutic responses in patients with hepatocellular carcinoma and breast cancer. Using an in vitro exposure system replicating the levels of exposure achieved in humans, we have described a phenotype in HCC cells following RF EMF exposure that included proliferative inhibition, modulation of gene expression, and disruption of the mitotic spindle. This phenotype was specific for HCC cells exposed to HCC-specific RF EMF at exposure levels ranging from 0.03 to 0.4 W/kg. Methods: HCC cells were exposed to 27.12 MHz electromagnetic fields modulated at specific frequencies from 400 Hz to 21 kHz, previously identified in HCC patients. MicroRNA arrays compared exposed and control groups of HCC cells, with microRNA validation followed by Western blot of target genes and proteins. HCC xenografts were injected subcutaneously in NOD SCID mice. Following palpable tumor establishment, mice were exposed to HCC-specific RF EMF at a specific absorption rate of 0.4 W/kg, euthanized following excessive tumor burden, and evaluated by immunohistochemistry. Results: We identified increased levels of miRNAs targeting proteins belonging to the PI3K pathway, specifically IP3/DAG signaling and intracellular calcium release. This pathway is frequently disrupted in HCC and breast cancer, making it an excellent candidate for modulation by RF EMF; furthermore, downstream effects include: cell cycle progression, proliferation, inhibition of apoptosis, and cell migration. We observed tumor shrinkage in mice exposed to HCC-specific modulation frequencies and residual xenograft tumor cells were infiltrated with fibrous tissue and showed significantly decreased proliferation and increased apoptosis. There was no evidence of altered cell proliferation or fibrosis in other organs. Conclusion: These findings are the first evidence of the efficacy and safety of RF EMF in HCC using a subcutaneous xenograft model and uncover a novel mechanism that controls cancer cell growth in vivo at specific modulation frequencies, possibly through modulation of PI3K signaling and downstream release of intracellular calcium. Citation Format: Hugo Jimenez, Jacquelyn W. Zimmerman, Michael J. Pennison, Ivan Brezovich, Nengjun Yi, Celeste T. Yang, Ryne Ramaker, Devin Absher, Richard M. Myers, Niels Kuster, Frederico P. Costa, Alexandre Barbault, Boris Pasche. Cancer cell proliferation is inhibited by specific modulation frequencies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2013-5612 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.</jats:p