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LPA Increases Tumor Growth and Bone Destruction Through Enhancement of Osteoclastogenic Cytokines
Lindholm, P. F.,Hwang, Y. S. Potamitis Press 2016 Anticancer research Vol.36 No.1
<P>Background: Lysophosphatidic acid (LPA) production in osteoblasts has multiple effects on osteoclast formation and function and raises the possibility that LPA may serve as a signaling molecule for the reciprocal conversation of both osteoblasts and osteoclasts within the tumor-bone microenvironment for bone resorption. However, little is known on the effect of LPA in regulating the function of both cancer cells and osteoclasts in the bone microenvironment. Materials and Methods: PC-3 tumor growth and bone destruction upon LPA administration were observed in a mouse calvarium xenograft. The osteoclastogenic cytokines produced by LPA-stimulated prostate cancer cells were also defined. Results: LPA administration was found to increase PC-3 tumor growth and bone destruction in a mouse calvarium xenograft. Using a cytokine antibody array, LPA highly stimulated the expression and release of osteoclastogenic cytokines from PC-3 cells. Conditioned medium from LPA-stimulated PC-3 cells containing enhanced levels of osteoclastogenic cytokines facilitated osteoclast formation. Histopathologically, LPA administration supports the erosive type of bone destruction by PC-3 prostate cancer cells. Conclusion: LPA is a critical regulator in the tumor-bone microenvironment and may be a therapeutic target for patients with prostate cancer. In addition, LPA-enhanced osteoclastogenic cytokines are critical to therapeutic strategies targeting osteolytic prostate cancer.</P>
Constitutive and Inducible Expression of Invasionrelated Factors in PC-3 Prostate Cancer Cells
황영선,Paul F. Lindholm 대한암예방학회 2015 Journal of cancer prevention Vol.20 No.2
Background:Tumor growth and invasion are interconnected with the tumor microenvironment. Overexpression of genes that regulate cancer cell invasion by growth factors, cytokines, and lipid factors can affect cancer aggressiveness. A comparative gene expression analysis between highly invasive and low invasive cells revealed that various genes are differentially expressed in association with invasive potential. In this study, we selected variant PC-3 prostate cancer cell sublines and discovered critical molecules that contributed to their invasive potential. Methods: The high invasive and low invasive variant PC-3 cell sublines were obtained by serial selection following Matrigel-coated Transwell invasion and were characterized by Transwell invasion, luciferase reporter assay, and Rhotekin pull-down assay. Lysophosphatidic acid (LPA) was added to the cultures to observe the response to this extracellular stimulus. The essential molecules related with cancer invasiveness were detected with Northern blotting, quantitative reverse transcription-polymerase chain reaction, and cDNA microarray. Results:Highly invasive PC-3 cells showed higher nuclear factor kappa B (NF-κB), activator protein 1 (AP-1) and RhoA activities than of low invasive PC-3 cells. LPA promoted cancer invasion through NF-κB, AP-1, and RhoA activities. Thrombospondin-1, interleukin-8, kallikrein 6, matrix metalloproteinase-1, and tissue factor were overexpressed in the highly invasive PC-3 variant cells and further upregulated by LPA stimulation. Conclusions:The results suggest that the target molecules are involved in invasiveness of prostate cancer. These molecules may have clinical value for anti-invasion therapy by serving as biomarkers for the prediction of aggressive cancers and the detection of pharmacological inhibitors.
Vuokko, Aki,Karvala, Kirsi,Suojalehto, Hille,Lindholm, Harri,Selinheimo, Sanna,Heinonen-Guzejev, Marja,Leppamaki, Sami,Cederstrom, Sebastian,Hublin, Christer,Tuisku, Katinka,Sainio, Markku Occupational Safety and Health Research Institute 2019 Safety and health at work Vol.10 No.3
Background: Chronic nonspecific symptoms attributed to indoor nonindustrial work environments are common and may cause disability, but the medical nature of this disability is unclear. The aim was to medically characterize the disability manifested by chronic, recurrent symptoms and restrictions to work participation attributed to low-level indoor pollutants at workplace and whether the condition shares features with idiopathic environmental intolerance. Methods: We investigated 12 patients with indoor aire-related work disability. The examinations included somatic, psychological, and psychiatric evaluations as well as investigations of the autonomic nervous system, cortisol measurements, lung function, and allergy tests. We evaluated well-being, health, disability, insomnia, pain, anxiety, depression, and burnout via questionnaires. Results: The mean symptom history was 10.5 years; for disabling symptoms, 2.7 years. Eleven patients reported reactions triggered mainly by indoor molds, one by fragrances only. Ten reported sensitivity to odorous chemicals, and three, electric devices. Nearly all had co-occurrent somatic and psychiatric diagnoses and signs of pain, insomnia, burnout, and/or elevated sympathetic responses. Avoiding certain environments had led to restrictions in several life areas. On self-assessment scales, disability showed higher severity and anxiety showed lower severity than in physician assessments. Conclusion: No medical cause was found to explain the disability. Findings support that the condition is a form of idiopathic environmental intolerance and belongs to functional somatic syndromes. Instead of endless avoidance, rehabilitation approaches of functional somatic syndromes are applicable.