Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen

Iguchi, Haruo; Onuma, Etsuro; Sato, Keita; Sato, Kanji; Ogata, Etsuro

doi:10.1002/ijc.1425

Cited by 57 publications

(55 citation statements)

References 21 publications

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“…Moreover, high-skilled operation such as cardiac injection and tail vein injection are needed, which was accompanied by high animal mortality and lower success rate [35][36][37]. With regard to the A549 CD133 + cells, it could be easily obtained through flow cytometry and cells inoculated subcutaneously in nude mouse could be employed to establish spontaneous liver metastasis model.…”

Section: Discussionmentioning

confidence: 99%

CD133 positive cells isolated from A549 cell line exhibited high liver metastatic potential

Zhang¹,

Yang²,

Sun³

et al. 2014

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Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapy. In present study, we identified a subpopulation of cells isolated from the A549 cell line with marker CD133. In vivo results showed that A549 CD133 + cells displayed high liver metastatic potential. Severe liver cell damage with tumor cell invasion revealed by pathological examination and these changes were consistent with the results of serological tests where the plasma GPT and GOT level are significantly higher than that of the control group. Compared with A549 cells, A549 CD133 + cells expressed high levels of VEGF and exhibited high migration and invasion capability. In conclusion, we first reported that A549 CD133 + cells exhibited characteristic of high liver metastatic potential which makes it be a suitable model for further study of liver metastasis of lung adenocarcinoma and provide a potential platform for antimetastatic drug discovery or evaluation. Key words: human lung adenocarcinoma, liver metastasis, migration, invasion, CD133Lung cancer is one of the most aggressive neoplasms in the world [1]. Despite management and treatment of lung cancer has been improved these years, but the prognosis remains poor, the 5-year survival rate of non-small cell lung cancer (NSCLC) is no more than 15 % [2]. Approximately 50 % of NSCLC patients with stage I and II will die from recurrent disease despite conventional therapy, and nearly 70% of lung cancer patients will die from metastatic disease, even after surgical resection of the primary tumor, radiation therapy, and chemotherapy [3]. Thus, it is important to find novel effective therapies to inhibit lung cancer metastasis.The most common four metastatic sites of patients with solitary metastatic NSCLC were: bone, liver, kidney and spleen [3]. Nevertheless, the mechanism of which lung adenocarcinoma selectively disseminated to certain organs remains unknown. However, experimental reproducible animal models facilitate to understand the process of metastasis and can provide suitable models for basic or preclinical studies.Different kinds of cancer metastasis model have been published yet. Early in 1996, Iguchi H et al [4] have established lung cancer metastasis model with human lung squamous cell carcinoma-derived cells (HARA). In 1959, Leduc [5] was the first to describe liver metastasis in mice after injection of hepatoma carcinoma cells in the spleen. Moreover, the liver metastasis models in nude mice of colon carcinoma have been successfully established [6,7]. Early studies in immunodeficient mice illustrated that subcutaneous injection of tumor cells seldom give rise to liver metastases [8].However, no lung adenocarcinoma liver metastasis model has been published so far. CD133 as a marker of cancer stem cells (CSCs) has been demonstrated in many cancers including lung cancer [9][10][11][12][13]. The CSCs theory indicated that subpopulation of tumor cells with stem or progenitor cell characteristics c...

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Section: Discussionmentioning

confidence: 99%

CD133 positive cells isolated from A549 cell line exhibited high liver metastatic potential

Zhang¹,

Yang²,

Sun³

et al. 2014

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“…Both polyclonal and monoclonal antibodies that neutralize PTHrP exerted anti-hypercalcemic and anticachectic effects in animal models [51][52][53]. Onuma et al generated a humanized anti-PTHrP monoclonal antibody [54].…”

Section: Orexigenic Neuropeptides (Npy Agrp Orexins Mch) In Anorexmentioning

confidence: 99%

Hypothalamic Neuropeptides and Appetite Response in Anorexia-Cachexia Animal

Ueta¹,

Hashimoto²,

Onuma

et al. 2007

Endocr J

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CACHEXIA, characterized by anorexia and marked weight loss, is a complex syndrome in patients with inflammatory disease and cancer. In particular, the pathogenesis of cancer cachexia is a multifactor syndrome that includes reduced food intake, alteration in energy and substrate metabolism in the host and accelerated fat and muscle loss [1]. As anorexia-cachexia syndrome compromises the quality of life and contributes to mortality in patients, it is important to examine the essential mechanisms of the syndrome in order to develop effective therapeutics even though anorexiacachexia syndrome may be caused by multiple factors.In this review, we focus on the hypothalamic neuropeptide gene expression in an anorexia-cachexia animal model because neuropeptides in the hypothalamus may be the key molecules that regulate the appetite and feeding behavior in cancer anorexia-cachexia syndrome [2] as well as in normal conditions [3,4]. Quantitative changes in neuropeptides gene expressions in the hypothalamus and the relevance of their changes in abnormal nutritional conditions (e.g., negative energy balance) are reviewed and discussed by a comparison of three different types of anorexia and anorexia-cachexia animal models; dehydration-induced anorexia, bacterial lipopolysaccharide (LPS)-induced anorexia, and cancer-induced anorexia-cachexia syndrome. Hypothalamic neuropeptides related to appetite and feeding behaviorsIt is well established that appetite and feeding behaviors are primarily controlled by a feeding center, the lateral hypothalamic area (LHA), and a satiety center, the ventromedial hypothalamic nucleus (VMH), in the hypothalamus [5]. Recently, neural networks and chemical mediators among the hypothalamic nucleinot only the LHA and the VMH but also the arcuate nucleus (Arc) and the paraventricular nucleus (PVN)-related to feeding regulation have been studied by many investigators. Various kinds of neuropeptides as well as classic neurotransmitters such as dopamine and serotonin act as feeding regulatory factors in the neural networks at these sites [6].For example, centrally administered neuropeptide Y (NPY) strongly stimulates feeding in mice and rats [7]. Many studies have demonstrated that the expression of the NPY gene was markedly increased in the neurons of the Arc after food deprivation (starvation). This type of peptide is called an "orexigenic" neuropeptide. Orexins/hypocretins, which are produced in the neurons located in the LHA [5], are also potent orexigenic neuropeptides. On the other hand, proopiomelanocortin (POMC), which encodes α melanocyte-stimulating

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“…Fat and muscle contents were determined by measuring the weights of the epididymal adipose tissue and gastrocnemius muscle, as described. 8 Concentrations in the serum of calcium and albumin were determined with whole blood obtained from the abdominal aorta and an autoanalyzer (Hitachi 7170), and that of a1-acid glycoprotein was determined by a rat a1-acid glycoprotein EIA kit (Sceti, Tokyo, Japan). Serum levels of human cytokines (hIL-6, hIL-1b, hTNF-a, hLIF, hIL-8, hIL-5 and hIL-11) and rat cytokines [rIL-6, rIL-8 (GRO/CINC1), rTNF-a, and rIL-1b] were also determined with whole blood obtained from the abdominal aorta using ELISA kits [Quantikine human IL-6; Quantikine TNF-a; Quantikine human LIF; Quantikine human IL-5; Quantikine human IL-11; Quantikine TNF-a (R&D Systems, Minneapolis, MN); BIOTRAK human IL-b; BIOTRAK rat IL-6; BIOTRAK GRO/CINK1; and BIOTRAK rat IL-1b (Amersham, Aylesbury, UK)] and human IL-8 (TFB Inc., Tokyo, Japan) according to the manufacturers' instructions.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…However, animals carrying tumors that secreted PTHrP often showed not only hypercalcemia but also wasting. 8 These facts suggest that PTHrP plays important roles in wasting in addition to its systemic hypercalcemic effects. Because PTHrP has been shown to induce production of several proinflammatory cytokines, 9 it may activate cytokine networks, which may result in cachexia.…”

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confidence: 99%

Parathyroid hormone–related protein (PTHrP) as a causative factor of cancer‐associated wasting: Possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts

Onuma¹,

Tsunenari²,

Saito³

et al. 2005

Intl Journal of Cancer

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Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in a1-acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute-phase reactions, whereas anti-PTHrP antibody affected neither proinflammatory cytokine production nor acutephase reactions. Nevertheless, tumor resection and administration of anti-PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti-PTHrP antibody was associated with increased food consumption; increased body weight from antiPTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP-induced wasting syndrome. ' 2005 Wiley-Liss, Inc.Key words: parathyroid hormone-related protein; wasting; proinflammatory cytokine; acute-phase reaction; locomotor activity Cancer-associated wasting (cancer wasting) is a complex disease often associated with anorexia and cachexia and characterized by several metabolic and behavioral abnormalities, such as early satiety, weakness, fatigue, depression and weight loss. Cancer wasting occurs in about 10% of advanced cases of malignancy. It correlates with poor prognosis irrespective of tumor mass or tumor metastases 1 and affects the susceptibility to and tolerability of chemotherapy.2 Furthermore, cancer wasting is not easily resolved by forced caloric intake.3 Several factors are thought to be involved in cancer wasting. TNF-a, IL-1b, IL-6, LIF and IFN-c have been demonstrated to cause cachectic symptoms in animal models. 4 Activin, a member of the TGF-b gene family, was found to induce cachectic symptoms in mice.5 PIF, a sulfated glycoprotein that induces protein catabolism in isolated muscle cells, has been detected in serum samples from cachectic mice and from cancer patients.1 LMF, a homologue of the plasma Zn-a2 glycoprotein which induces lipid mobilization and catabolism in rats, has been isolated from the urine of cancer patients. 6 Nevertheless, the etiology of cancer cachexia is still not well...

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Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen

Cited by 57 publications

References 21 publications

CD133 positive cells isolated from A549 cell line exhibited high liver metastatic potential

CD133 positive cells isolated from A549 cell line exhibited high liver metastatic potential

Hypothalamic Neuropeptides and Appetite Response in Anorexia-Cachexia Animal

Parathyroid hormone–related protein (PTHrP) as a causative factor of cancer‐associated wasting: Possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts

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