Total parenteral nutrition and tumor growth in malnourished patients with gastric cancer.

AIMS AND BACKGROUND: Evidence that total parenteral nutrition (TPN) can stimulate tumor growth in humans is scanty and contradictory. The purpose of this study was to evaluate the impact of TPN on tumor cell proliferation in malnourished patients receiving preoperative TPN. METHODS: We evaluated variations in the S-phase cell fraction, defined as 3H-thymidine labeling index (TLI), before and after 10 days of TPN or non-administration of nutritional support in 19 malnourished patients (weight loss, > or = 10%) with gastric cancer. TLI was determined on endoscopic biopsies at the time of diagnosis, and subsequently on the operative specimen or through intraoperative sampling. RESULTS: At diagnosis, a higher median TLI value was observed in the control than in the TPN group. Administration of TPN enhanced tumor cell proliferation in 50% of patients; however, at surgery there was no difference in the median TLI value of the two groups. CONCLUSIONS: The TPN regimen seems to be associated with increased tumor cell proliferation, even though this stimulating effect was moderate and at surgery the TLIs of TPN patients and controls were not different. Although the potential stimulation probably has little consequence for patients receiving short-term preoperative nutrition, it may call for further investigation in cancer patients undergoing long-term home TPN.     

Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice

Groups of 15 mice of three different laboratory strains (BALB/c, C3H/He, DBA/2) were fed on a low iron diet (5 mg iron/kg diet), and three similar groups of 15 mice were maintained on a normal iron diet (312 mg iron/kg diet). When the low iron diet group became iron deficient, tumor cells (5 x 10(5) cells/mouse) of CA07-A (colon adenocarcinoma), HE129 (hepatoma), and M119 (mammary adenocarcinoma) were inoculated s.c. in BALB/c, C3H/He, and DBA/2 mice, respectively. All mice developed tumors, tumors grew more slowly, and the mean tumor sizes were smaller in the low iron diet group at nearly all weekly observations in all three strains of mice. No apparent differences in the behavior, activity (e.g., movement, climbing, running, grooming, etc.), and appearance were observed between low iron diet and normal iron diet mice. The mean body weight of mice at transplantation was less in the low iron than in the normal iron groups for the BALB/c strain but higher in the low iron groups of C3H/He and DBA/2 mice, indicating that food intake of mice on a low iron diet was not impaired. These results suggest that iron nutrition of the host affects tumor growth; tumor cells grow better in an iron-rich environment. This knowledge should be considered when designing treatment for patients with cancer. Iron oversupply in cancer patients might enhance tumor growth and adversely affect cancer therapy.     

Interleukin generation in experimental colon cancer of rats: effects of tumor growth and tumor therapy

The capacity of inbred W/Fu rats bearing syngeneic colon carcinomas to generate interleukin(s) (IL) was studied during primary tumor growth, after tumor resection, and during postresection immunotherapy. During local tumor growth, there was a significant decrease in the capacity of the host's adherent mononuclear cells to generate IL-1 and of peripheral blood mononuclear cells to generate IL-2 (16.6 and 23%, respectively, when compared to control animals; P less than .01). The presence of regional metastases or large primary tumor burden resulted in a further sharp fall in IL generation (0.9 and 10% for IL-1 and IL-2, respectively, when compared to control animals; P less than .01). With the use of three different doses of tumor inoculum, inhibition of IL generation was shown to occur when tumors were barely palpable. Decrease in IL correlated with tumor growth and not with the initial number of tumor cells injected. Tumor resection resulted in a rise in IL-2 generation from 36 to 64% of control animals' levels. Postresection immunotherapy with the use of an active specific immunization protocol successfully modulated IL-2 production to normal in animals protected from tumor recurrence. Animals that developed recurrent tumors despite immunization exhibited a continued inability to generate IL (mean values of IL-2 production compared to controls: 184% in animals free of recurrence after immunotherapy, 1% in animals developing recurrent tumors after immunotherapy; P less than .01). These results suggested that alterations in IL generation may lead to immune unresponsiveness during tumor growth. Active specific immunotherapy protecting animals from recurrence after primary tumor resection may be predicated on the successful modulation of IL level generation by host immunocytes.     

Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia.

The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.     

Substituting ornithine for arginine in total parenteral nutrition eliminates enhanced tumor growth.

Total parenteral nutrition (TPN) may enhance the growth of some tumors: this enhanced growth is associated with an increase in the erythrocyte polyamine levels. The effect of arginine in TPN on tumor growth was compared with ornithine using rats with a transplantable Ward colon tumor. The relationship of circulating arginine, ornithine, glutamine, and polyamines with tumor growth was investigated. For rats fed chow ad libitum, increasing tumor weights were associated with a linear decrease in the plasma arginine levels which was consistently lower than that of age-matched non-tumor bearing (NTB) rats; ornithine and lysine levels were not affected. Subsequent experiments suggest that plasma glutamine levels were also lower in tumor bearing rats. Pair-fed NTB rats had reduced arginine but not glutamine levels in plasma. TPN regimens with arginine or with ornithine substituted for arginine at two levels (equimolar [Orn-Em] or isonitrogenous [Orn-IN]) were given to colon tumor bearing rats for 8 days. The final tumor weight of rats which received the arginine-containing regimen (19.8 +/- 5.7 g, n = 4) (P less than 0.05) was significantly greater than the tumor weight of rats fed chow ad libitum (12.1 +/- 3.3 g, n = 6). The final tumor weights of Orn-EM (11.2 +/- 2.6 g, n = 4) or Orn-IN (11.6 +/- 0.8 g, n = 6) were similar to the chow-fed controls. The plasma arginine levels were elevated, compared with the control, when arginine was present in the regimen. The plasma arginine levels of rats which received Orn-EM or Orn-IN were lower than the controls. The plasma ornithine levels were not affected by arginine in the regimen but were elevated with increasing levels of ornithine in TPN. Plasma glutamine levels were decreased when arginine was present in the regimen but were elevated when ornithine was substituted for arginine. Erythrocyte putrescine was increased when either arginine or ornithine was included in the TPN regimens. These results demonstrate that while arginine in a parenteral regimen stimulates tumor growth, substituting ornithine for arginine in TPN does not enhance the growth of a transplantable colon tumor.     

Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis

A role of dietary bioactive components in bladder cancer prevention is biologically plausible because most substances or metabolites are excreted through the urinary tract and are consequently in direct contact with the mucosa of the bladder. We first determined antigrowth activity of genistein against poorly differentiated 253J B-V human bladder cancer cells in vitro. Genistein inhibited the cell growth in a time- and dose-dependent manner via G(2)-M arrest, down-regulation of nuclear factor kappaB (NF-kappaB), and induction of apoptosis. We also evaluated both genistin, which is a natural form of genistein, and the isoflavone-rich soy phytochemical concentrate (SPC) on the growth and metastasis of 253J B-V tumors in an orthotopic tumor model. Mice treated with genistin and SPC had reduced final tumor weights by 56% (P < 0.05) and 52% (P < 0.05), respectively, associated with induction of tumor cell apoptosis and inhibition of tumor angiogenesis in vivo. In addition, SPC treatment, but not genistin treatment, significantly inhibited lung metastases by 95% (P < 0.01) associated with significant down-regulation of NF-kappaB expression in tumor tissues and reduction of circulating insulin-like growth factor-I levels, suggesting that SPC may contain other bioactive ingredients that have antimetastatic activity. The results from our studies suggest that further clinical investigation should be warranted to apply soy phytochemicals, such as SPC, as a potent prevention regimen for bladder cancer progression. This orthotopic human bladder tumor model also provides a clinically relevant experimental tool for assessing potential preventive activity of other dietary components against bladder tumor growth and metastasis.     

Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy.

PURPOSE: The incidence of prostate cancer is frequent, occurring in almost one-third of men older than 45 years. Only a fraction of the cases reach the stages displaying clinical significance. Despite the advances in our understanding of prostate carcinogenesis and disease progression, our knowledge of this disease is still fragmented. Identification of the genes and patterns of gene expression will provide a more cohesive picture of prostate cancer biology. PATIENTS AND METHODS: In this study, we performed a comprehensive gene expression analysis on 152 human samples including prostate cancer tissues, prostate tissues adjacent to tumor, and organ donor prostate tissues, obtained from men of various ages, using the Affymetrix (Santa Clara, CA) U95a, U95b, and U95c chip sets (37,777 genes and expression sequence tags). RESULTS: Our results confirm an alteration of gene expression in prostate cancer when comparing with nontumor adjacent prostate tissues. However, our study also indicates that the gene expression pattern in tissues adjacent to cancer is so substantially altered that it resembles a cancer field effect. CONCLUSION: We also found that gene expression patterns can be used to predict the aggressiveness of prostate cancer using a novel model.     

Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients.

PURPOSE: Genetically altered cells could become widespread across the epithelium of patients with oral cancer, often in clinically and histologically normal tissue, and contribute to recurrent disease. Molecular approaches have begun to yield information on cancer/risk fields; tissue optics could further extend our understanding of alteration to phenotype as a result of molecular change. EXPERIMENTAL DESIGN: We used a simple hand-held device in the operating room to directly visualize subclinical field changes around oral cancers, documenting alteration to fluorescence. A total of 122 oral mucosa biopsies were obtained from 20 surgical specimens with each biopsy being assessed for location, fluorescence visualization (FV) status, histology, and loss of heterozygosity (LOH; 10 markers on three regions: 3p14, 9p21, and 17p13). RESULTS: All tumors showed FV loss (FVL). For 19 of the 20 tumors, the loss extended in at least one direction beyond the clinically visible tumor, with the extension varying from 4 to 25 mm. Thirty-two of 36 FVL biopsies showed histologic change (including 7 squamous cell carcinoma/carcinomas in situ, 10 severe dysplasias, and 15 mild/moderate dysplasias) compared with 1 of the 66 FV retained (FVR) biopsies. Molecular analysis on margins with low-grade or no dysplasia showed a significant association of LOH in FVL biopsies, with LOH at 3p and/or 9p (previously associated with local tumor recurrence) present in 12 of 19 FVL biopsies compared with 3 of 13 FVR biopsies (P=0.04). CONCLUSIONS: These data have, for the first time, shown that direct FV can identify subclinical high-risk fields with cancerous and precancerous changes in the operating room setting.     

塞来昔布对实验性结肠癌原位移植瘤生长及血管形成的影响

目的:探讨塞来昔布对实验性结肠癌原位移植瘤生长及血管形成的影响。方法:使用对数生长期的人结肠癌细胞(HT-29)于裸鼠皮下接种成瘤后原位种植。术后随机分为对照组(C组)及塞来昔布高、中、低剂量组(H、M、L组)共四组进行研究。结果:24只裸鼠实验期间无1只死亡,成瘤率为100%,比较各组原位移植瘤体积和瘤质量差异有统计学意义,P值均<0·05。L、M和H组的抑瘤率分别为25·30%、38·80%和76·92%,与对照组比较差异有统计学意义,P=0·000,且存在明显的剂量依赖。干预组瘤组织中MVD、VEGFmRNA、MMP-2mRNA和匀浆上清中PGE2含量与对照组相比差异有统计学意义,P值分别为0·050、0·050、0·050和0·010,随着剂量增加,MVD、VEGFmRNA、MMP-2mRNA和匀浆上清中PGE2含量逐渐降低。瘤组织中PGE2含量与瘤质量,以及MVD与VEGFmRNA、MMP-2mRNA均存在显著的正相关性,r=0·8814,P=0·000;r=0·8573,P=0·000;r=0·6427,P=0·001。结论:塞来昔布通过抑制人结肠癌裸鼠原位移植瘤环氧化酶-2活性,抑制PGE2合成、VEGFmRNA和MMP-2mRNA表达,抑制肿瘤的血管形成,从而对结肠癌的生长有抑制作用。     

Oncogenes and tumor growth factors in breast cancer. A minireview

Five oncogenes have been implied as having a role in human breast tumorigenesis: int-2, c-erbB-2 (HER-2), c-myc, c-Ha-ras and the recessive Rb-1. As far as the function and biochemistry of these oncogenes have been studied, they act at different levels and have totally different functions in the cells. They are normally cellular genes, likely to have important functions in normal cell growth or differentiation. In the tumors their regulation or function is altered, due to a wide class of mutations. The oncogenes may cooperate to result in the malignant cell phenotype. However, different oncogenes are mutated in different tumors, so that the tumors show a variable pattern at the molecular level, underlining the individuality of these tumors already described as differences in histopathology, hormone receptor expression and clinical course. The main importance of the oncogene studies is still to reveal basic pathogenetic mechanisms. When appropriate it is important to test diagnostic or prognostic significance of the oncogene mutations.     

Enhanced tumor growth in experimental whole body hyperthermia

The purpose of this study was to investigate the interaction of heat and chemotherapy in experimental whole body hyperthermia (WBH). A vascular technique of extracorporeal perfusion was employed to rapidly elevate body temperature in rabbits carrying the transplantable VX-2 carcinoma. Hyperthermia (> 41°C) was achieved in a mean time of 28 minutes. Tumor-bearing rabbits receiving WBH alone exhibited poor mean survival (14 days) relative to untreated tumor-bearing animals (32 days) and the group receiving IV Cis-platinum alone (50 days) (NS, p < .05 respectively). WBH with Cis-platinum was intermediate in terms of mean survival (30 days, NS) between the WBH alone and Cis-platinum alone groups. In this experimental model we have determined WBH to be a detrimental form of cancer therapy. Its action appears to enhance tumor proliferation, resulting in rapid animal demise. In light of these findings a reevaluation of clinical WBH may be warranted.     

Epidermal growth factor receptor structural alterations in gastric cancer

Background  

EGFR overexpression has been described in many human tumours including gastric cancer. In NSCLC patients somatic EGFR mutations, within the kinase domain of the protein, as well as gene amplification were associated with a good clinical response to EGFR inhibitors. In gastric tumours data concerning structural alterations of EGFR remains controversial. Given its possible therapeutic relevance, we aimed to determine the frequency and type of structural alterations of the EGFR gene in a series of primary gastric carcinomas.     

Effects of enteral and parenteral nutrition on tumor response to chemotherapy in experimental animals

The effects of oral and intravenous nutrition on host and tumor responses to graded doses of methotrexate (MTX) were evaluated in 150 adult Sprague-Dawley rats. All animals were inoculated with Walker-256 carcinosarcoma and were fed a regular diet for ten days before assigning them to three dietary groups. Group I (n = 64) received a constant intravenous infusion of 30% dextrose-5% amino acids (IVH), group II (n = 64) received an identical solution orally ad libitum, and group III (n = 22) received a regular diet ad libitum. Animals in groups I and II were then divided into three subgroups each that received either 20 mg/kg, 40 mg/kg, or 60 mg/kg of MTX intramuscularly. Ten days later, all surviving animals were killed. Animals fed the 30% dextrose-5% amino acid diet orally and given 20 mg/kg and 40 mg/kg of MTX lost slightly less body weight when compared with their IVH counterparts. In the 60 mg/kg treatment group, orally fed animals lost 52 gm of body weight compared with 23 gm in IVH animals. IVH rats given 20 mg/kg and 40 mg/kg of MTX demonstrated significant inhibition of tumor growth and decreased tumor weight/body weight ratios when compared with orally fed rats. No improvement in tumor response to 60 mg/kg of MTX was observed, however, when IVH animals were compared with orally fed rats. In a second study, nutrient intake was maintained at a constant level by intravenous infusion in one group and intrajejunal infusion in another group of tumor-bearing rats. Host and tumor responses to 20 mg/kg of MTX were similar in both groups of animals.     

Genomic alterations in tumor tissue and ctDNA from Chinese pancreatic cancer patients

Though the genomic feature of pancreatic cancer has been comprehensively studied in western patients, the genetic feature of Chinese patients is poorly clarified. In this study, a total of 225 pancreatic cancer patients were enrolled, mainly pancreatic ductal adenocarcinoma (PDAC, 97.33%). 140 patients (62.22%) provided sufficient tumor tissues for genomic analysis, and the rest (37.78%) were provided serum instead. Utilizing target next-generation sequencing (NGS), we analyzed genomic alterations of 618 selected genes. Corresponding data in the TCGA database were also analyzed here. In total, 26 (11.61%) patients had pathogenic or likely pathogenic germline variants, mainly (84.62%) involved genes in the DNA damage repair (DDR) pathway. The mean and median counts of somatic alterations per sample were 6.28 and 5, respectively. The most frequently mutated genes in our cohort were KRAS, TP53, CDKN2A, SMAD4, FBXW7 and ARID1A, revealing a significantly different prevalence of genes including KRAS, CDKN2A, ARID1A, NOTCH1, ARID1B than the corresponding data in the TCGA database. 39.11% of patients were identified with actionable alteration and the ratio was not significantly different between tissue and serum samples. 22.67% of patients harbored DDR gene alterations, which were associated with a higher tumor mutation burden. We also found that all the DDR alterations were not correlated with the overall survival and immune and stroma score, but the changes in NK cells and follicular T cells were identified in samples with DDR changes according to TCGA database. In summary, we identified a distinct genomic feature of Chinese pancreatic cancer patients by comparing with the data in TCGA database, and suggested the role for genetic testing using tissue or ctDNA samples in decision-making process. DDR alterations were associated with a higher tumor mutation burden and the significantly higher counts of NK cells in DDR altered samples may raise the attention in future related drugs development.     

Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells.

PURPOSE: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). EXPERIMENTAL DESIGN: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. RESULTS: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. CONCLUSION: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.