Telomere dysfunction and tumour suppression: the senescence connection

Long-lived organisms such as humans have evolved several intrinsic tumour suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem-cell compartments. One of these anticancer barriers is the telomere, a specialized nucleoprotein complex that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.     

The steroid hormone receptors in tumors of adipose tissue

The clinical evidence suggests that the steroid hormones may influence the biologic course of tumors of soft tissue. In an attempt to characterize the possible steroid hormone dependency of soft tissue, we studied the incidence and distribution of cytosolic receptors for the steroid hormones in benign and malignant tumors of adipose tissue origin. All specimens were assayed for the steroid hormone receptors by charcoal dextran technique and analyzed by the method of Scatchard. The results show a high incidence of cytosolic estrogen and glucocorticoid receptors in tumors of adipose tissue origin except in lipoma and well differentiated liposarcoma. The binding parameter of these receptors suggests that the receptors may be responsive to physiologic steroid hormonal milieu.     

Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR −/−) participating in a breast cancer case–control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER−/PR− breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER−/PR− breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER−/PR− breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.     

Growth of endometrial cancer and hormone

Proliferation and differentiation of the normal endometrium are orderly regulated by female sex steroid hormones. In this connection, development and growth of endometrial cancer have also thought to be controlled in part by sex steroid hormones. Furthermore, some of the sex steroid hormones, progesterone, for example, are used as therapeutic agents in the management of endometrial cancer. The role of estrogen as a promotion factor of endometrial cancer is understood by unopposed estrogen hypothesis, and relative excess of estrogen unopposed by gestagen is regarded as an important factor for the development of endometrial cancer. High dose administration of gestagen has been used as a therapeutic agent of endometrial cancer over these three decades, and now the oral administration of medroxyprogesterone acetate (MPA) is mainstay, with response rate of approximately 30%. However, recently some cases with serious side effect, mainly thrombosis, have been reported. These cases should be regarded as a grave warning to easy usage of MPA. Therefore, the search for more effective and safe way for clinical application have to be requested; for example, clarification of the precise mechanism of anti-tumor effect of MPA on endometrial cancer or development of new hormonal therapeutic agents. Moreover, basic research in the field of cancer and hormone may create a new era in cancer therapy in the future.     

Growth hormone and experimental cancer cachexia

Plasma levels of growth hormone (GH) and the effect of GH treatment have been evaluated in adult nongrowing sarcoma-bearing mice (C57BL/6J). Prepubertal tumor-bearing mice, tumor-bearing hypophysectomized Sprague-Dawley rats, and malnourished non-tumor-bearing animals served as additional groups of study and control animals. Adult sarcoma-bearing mice showed an increase in plasma levels of GH early following tumor implantation. GH levels increased further with tumor progression. The anorexia and the state of malnutrition in sarcoma-bearing mice were the major factors behind increased GH levels. Muscle wasting and body composition in the tumor-bearing host were not improved by GH treatment at doses that increased growth rate in normal growing mice with intact pituitaries or partially normalized growth rate in hypophysectomized rats. Exogenous GH supported tumor growth and host body growth to the same extent in hypophysectomized rats. Exogenous GH in excess of endogenous GH did not stimulate tumor growth further. It is suggested that increased GH production in a tumor-bearing host acts in concert with other hormones to stimulate endogenous substrate mobilization and in tumor-bearing animals to prevent substrate deficiency and hypoglycemia. On the basis of this conclusion, it is unlikely that GH supplementation to a freely eating tumor-bearing host will support replenishment of host tissues.     

Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer

COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What''s more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.     

Growth hormone inhibits tumor metastasis

The effect of growth hormone on tumor growth and metabolism in the tumor-bearing host is unknown. This study was done to determine the effect of recombinant growth hormone on primary tumor growth, tumor metastasis, and carcass weight in tumor-bearing animals. Twenty-seven female Lobund/Wistar rats with subcutaneous prostate tumor implants (PA-III) were randomized to receive a standard protein diet (22.0% protein; 4.27 kcal/g) or an isocaloric, protein-depleted diet (0.03% protein; 4.27 kcal/g) ad libitum orally. One half of the animals in each group were randomized to receive daily injections of either recombinant growth hormone (1000 mU/kg/day intramuscularly) or placebo (saline) for 14 days. A significant increase in body weight was observed in growth hormone-treated animals without acceleration of primary tumor growth. Spontaneous pulmonary metastasis was inhibited significantly in animals in both dietary groups treated with growth hormone. Thus, growth hormone selectively supports host growth and inhibits pulmonary metastasis in this tumor-bearing animal model. The potential metabolic effects and clinical consequences of treating cancer patients with growth hormone is discussed.     

Ha-Ras(G12V) induces senescence in primary and immortalized human esophageal keratinocytes with p53 dysfunction

Oncogenic Ras induces premature senescence in primary cells. Such an oncogene-induced senescence involves activation of tumor suppressor genes that provide a checkpoint mechanism against malignant transformation. In mouse, the ARF-p53 pathway mediates Ha-Ras(G12V)-induced senescence, and p19(ARF-/-) and p53(-/-) cells undergo transformation upon Ras activation. In addition, mouse cells, unlike human cells, express constitutively active telomerase and have long telomeres. However, it is unclear how Ras activation affects human cells of epithelial origin with p53 mutation and/or telomerase activation. In order to address this question, Ha-Ras(G12V) was expressed ectopically in primary as well as hTERT-immortalized human esophageal keratinocytes stably expressing dominant-negative p53 mutants. In human esophageal keratinocytes, we found that Ha-Ras(G12V) induced senescence regardless of p53 status and telomerase activation. Ras activation resulted in changes of cellular morphology, activation of senescence-associated beta-galactosidase, and suppression of cell proliferation, all coupled with reduction in the hyperphosphorylated form of the retinoblastoma protein (pRb). Furthermore, Ha-Ras(G12V) upregulated p16(INK4a) and downregulated cyclin-dependent kinase Cdk4 in human esophageal keratinocytes. Thus, Ras-mediated senescence may involve distinct mechanisms between human and mouse cells. Inactivation of the pRb pathway may be necessary for Ras to overcome senescence and transform human esophageal epithelial cells.     

细胞衰老与肿瘤发生

细胞衰老是细胞周期抑制的极端稳定状态,DNA损伤和癌基因活化均可导致细胞衰老.癌基因诱导性衰老被认为是防止肿瘤发生的重要屏障.最近发现,癌基因诱导性细胞衰老发生于肿瘤形成的早期阶段.在癌变前肿瘤病变中,有丰富的衰老肿瘤细胞,而在恶性肿瘤中则显得稀少.因此,衰老是恶变前肿瘤细胞的重要特征,将在癌症的早期诊断和预后方面彰显重要价值.     

Cell senescence and cancer

Historically, the senescent state has been associated with, and was named after, the cell-cycle arrest that occurs after cells have undergone an intrinsically defined number of divisions in vitro. More recently, however, it has been shown that extrinsic factors, including those encountered in normal tissue-culture environments, can prematurely induce an indistinguishable senescent phenotype. In this review, we discuss the pathways of cell senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer.     

细胞衰老与肿瘤

衰老是细胞脱离细胞周期并不可逆地丧失增殖能力后进入的一种相对稳定的状态,是正常细胞的必然归宿。研究表明,随着细胞衰老,许多基因的表达发生变化,这包括激活因子的抑制和生长抑制因子的过表达,以及下游途径的干预;同时端粒和端粒酶也发生改变。目前的研究结果还表明,衰老与肿瘤的发生和诊治存在密切关系。除对纤维原细胞开展研究外,还涉及到更多类型的细胞,这为更好地确定细胞衰老在肿瘤发生中的作用提供理论基础,同时也可能为肿瘤的抑制提供一个新思路。