Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.
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PMID:Interleukin-6 serum level correlates with survival in advanced gastrointestinal cancer patients but is not an independent prognostic indicator. 1117 80

Two types of colorectal cancer with distinct morphologies have been described in recent studies: polypoid growth type (PG-type) and non-polypoid growth type (NPG-type). We hypothesize that the morphologic differences may correspond to additional biological distinctions. Ratios of sialyl Lewisa (CA 19-9), sialyl Lewisx (SLX), or carcinoembryonic antigen (CEA) in the venous blood drainage from the tumor to that of the respective antigen in the peripheral venous blood (d/p ratio) was examined in order to ascertain whether or not the ratio is correlated with either the PG-type or NPG-type colorectal tumor growth pattern. Blood samples from 118 patients with colorectal cancer were obtained from a peripheral vein and from the tumor drainage vein during surgical excision of the tumor. Statistical tests were conducted by univariate and multivariate (logistic regression) analyses. Among the cancers examined there were 17 PG-type (14.4%) and 101 NPG-type (85.6%). NPG-type cancers had a higher frequency of moderately differentiated adenocarcinoma cells and T3/T4 tumors than PG-type cancers (P<0.0001 and P<0.0001, respectively). NPG-type cancers had a more advanced stage than PG-type cancers (P=0.0007). The d/p ratio of SLX in NPG-type cancers was significantly higher than that in PG-type cancers (P=0.028). Multivariate logistic regression analysis showed that three variables, namely histologic type, T factor, and d/p ratio of SLX, were independently related to tumor growth patterns. In conclusion, NPG-type cancers are characterized by a high SLX d/p ratio, which may be at least partly responsible for a different tumor progression pattern compared to other cancer types.
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PMID:Increased serum level of sialyl Lewis(x) antigen in blood from the tumor drainage vein in patients with non-polypoid growth type of colorectal cancer. 1137 Aug 35

p53 Antibodies (p53-Abs) have been detected in the serum of a proportion of colorectal cancer (CRC) patients. It is not yet known at which stage during colorectal tumor progression p53-Abs appear in the serum. The utility of these antibodies as markers for CRC prognosis remains to be clarified. Using a quantitative enzyme-linked immunosorbent assay, we analyzed serum samples from 998 CRC patients and from 211 patients with polyp. Levels of p53-Abs were defined as negative (<10 U/microL), low (10-76 U/microL) and high (>76 U/microL). Overall, 13.0% of CRC patients and less than 1% of polyp patients had increased serum p53-Ab levels. High p53-Ab levels were only seen in patients with invasive carcinomas. The parameters that were significantly and independently associated with a greater frequency of high p53-Ab levels were the left colon (odds ratio [OR] = 3.4; 95% CI = 1.1-10.5), the rectum (OR = 2.9; 95% CI, 1.0-8.8) and advanced lymph node metastasis (OR = 4.6; 95% CI, 2.2-9.6). In univariate analysis, patients with high p53-Ab levels had a shorter survival times than did those without (p = 0.007). However, the significant effect disappeared in a Cox regression model adjusting for sex, age, tumor location, carcinoembryonic antigen levels, gross findings, histologic grade, mucin production and TNM stage. Thus, autoantibodies against p53 occur with tumor progression in multistep colorectal carcinogenesis and increase with advanced node metastasis. Furthermore, the seemingly adverse effect of high p53-Ab levels on the survival of CRC patients may be explained by other prognostic factors.
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PMID:Humoral response to p53 in human colorectal tumors: a prospective study of 1,209 patients. 1174 89

Kupffer cells, residential liver macrophages, have binding sites for carcinoembryonic antigen (CEA), but their role in metastatic liver tumor progression has not been well addressed clinically. Liver macrophages were analyzed morphometrically and their relationship with CEA and tumor microvessel density (MVD) was examined in 71 patients who underwent macroscopic curative hepatectomy for metastatic liver tumors from colorectal cancer. In paraffin-embedded sections, MVD was evaluated by CD34-positive cell counts, liver macrophages visualized using anti PG-M1 (CD68) antibody were analyzed, and membrane-bound CEA was assessed by immunoreactivity of tumor cells for CEA. The area of liver macrophages in peritumoral regions (43.0 +/- 11.6 microm2) was significantly larger than that in non-tumor regions (25.2 +/- 24.2 microm2) (P < 0.0001). The liver macrophage density in peritumoral regions was 154 +/- 49 per field, and was significantly higher than in non-tumor regions (74 +/- 24 per field) (P < 0.001). The density and the area of liver macrophages had no correlation with serum CEA levels and the degree of tumor CEA expression. A weak positive correlation was observed between MVD and liver macrophage density (P = 0.0104, Spearman rank correlation coefficient = 0.31). Cox multivariate regression analysis showed that MVD greater than 50 (P = 0.0233, hazard ratio = 2.463), and the area of liver macrophages larger than 40.9 microm2 (P = 0.0485, hazard ratio = 2.127), were significant independent prognostic factors. The present morphometric analysis suggests that the liver macrophages are accumulated and activated in peritumoral regions in patients with colorectal liver metastasis and this accumulation and activation of liver macrophages, with which soluble or membrane-bound CEA might not be associated, are related with patients' poor prognosis.
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PMID:Morphometric analysis of liver macrophages in patients with colorectal liver metastasis. 1196 75

It has been suggested that carcinoembryonic antigen (CEA) enhances metastatic seeding of colon cancer cells due to its homo- and heterophilic binding properties. Our recent finding that endogenous CEA protects colon cancer cells against apoptosis suggests a more complex role of CEA in cancer progression. In this study we compared the in vitro effects of endogenous CEA on tumor cell aggregation and cell cycle regulation of human HT29 colon cancer cells with the corresponding in vivo effects, i.e. tumor cell seeding and formation of metastatic lesions. Stable expression of CEA targeted ribozymes (Rz) under control of a tet-off promoter system allowed regulation of CEA levels on the mRNA and protein level by 50%. Downregulation of CEA levels inhibited tumor cell aggregation by 70%. In accordance with previous studies, reduction of CEA levels increased in vitro the apoptotic rate and reduced colony formation by 30% to 50%. To determine the in vivo effect of CEA-dependent aggregate formation and its growth regulating role under apoptotic stress, HT29 cells with high and low CEA levels, respectively, were injected into nude mice. Immunostaining of lung microsections revealed similar numbers of tumor cells one hour after injection. 24 h later virtually all cells were removed from the lung in both groups. However, after 6 weeks all doxycycline treated mice (Rz off = CEA high) showed 14.5 +/- 4.6 metastatic lung lesions/mouse while 0.2 +/- 0.2 lesions/mouse appeared in the untreated group (Rz on = CEA low) (P < 0.001). Our study demonstrates a multifunctional role of CEA and indicates a prometastatic role of CEA independent of its adhesive function possibly due to its anti-apoptotic function.
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PMID:Inhibition of endogenous carcinoembryonic antigen (CEA) increases the apoptotic rate of colon cancer cells and inhibits metastatic tumor growth. 1196 79

The aim of this study was to develop a murine model of human colon carcinoma (hCC) and to ascertain the potential of cellular immunotherapy in this model. Fragments of hCC obtained at surgery from 6 patients were transplanted under the kidney capsule of lethally irradiated CB6 mice radioprotected with severe combined immunodeficient (SCID) mice bone marrow. Tumor xenografts conserved their malignant behavior in the new environment, invading the mouse kidney parenchyma and expanding into the peritoneal cavity and adjacent tissues. Their growth was typically exponential, and they expanded to dimensions that allowed their subsequent fragmentation and passage to further preconditioned mice. Human carcinoembryonic antigen (hCEA) was detected on the implanted tumor and at occasionally spontaneous lung metastases. Most significantly, high levels of this tumor marker were detected in the sera of tumor-bearing mice, providing a useful tool, which allowed long-term experiments, monitoring of tumor progression, and its response to some treatment modalities. For instance, complete resection of the transplanted tumors, by means of nephrectomy, resulted in the disappearance of hCEA from mice sera within 2 weeks. Similarly, adoptive transfer of allogeneic human peripheral blood mononuclear cells (PBMC) into the peritoneum of tumor-bearing mice, resulted in their rapid engraftment, infiltration of tumor mass, and a significant drop of hCEA levels in mice serum, accounting for inhibition of tumor growth. We suggest that this novel model of human colon carcinoma affords the opportunity for in vivo evaluation of different preclinical treatment modalities, particularly, those involving manipulation with immune effector cells.
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PMID:Human colon adenocarcinoma in the SCID/CB6 radiation chimera is susceptible to adoptive transfer of allogeneic human peripheral blood mononuclear cells. 1259 Jul 3

The carcinoembryonic antigen (CEA) is an attractive target for immunotherapeutic purposes because of its expression profile, its role in tumor progression, and its immunogenicity. However, CEA belongs to the CD66 immunoglobulin super-gene family that comprises highly homologous molecules expressed on leukocytes, making CEA a potential autoantigen expressed on hematopoietic cells. We used a MHC class II epitope prediction algorithm (TEPITOPE) to select 11 sequence segments of CEA that could form promiscuous CD4(+) T-cell epitopes and used synthetic peptides corresponding to the predicted sequences to propagate in vitro CD4(+) T cells from healthy donors and colon cancer patients. CD4(+) T cells from all subjects strongly recognized the sequence segment (LWWVNNQSLPVSP), repeated at residues 177-189 and 355-367. Importantly, we demonstrated that this highly immunodominant region contains a naturally processed epitope(s). Cross-recognition experiments with peptide analogues present on the CD66 homologous proteins showed that CEA(177-189/355-367)-specific CD4(+) T cells did not recognize the analogues, demonstrating that recognition of the immunodominant epitope is CEA specific. These data suggest that the repertoire of CEA(177-189/355-367)-specific CD4(+) T cells might have been shaped by a selective process to exclude CD4(+) T cells specific for CD66 homologues expressed on leukocyte, while preserving the CEA-specific repertoire. The features of strong immunogenicity and immunodominance in the absence of potential induction of autoimmunity make the identified CEA epitope of particular interest for the development of antitumor vaccines.
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PMID:CD4(+) T cells from healthy subjects and colon cancer patients recognize a carcinoembryonic antigen-specific immunodominant epitope. 1467 13

Tumor necrosis factor-alpha (TNF-alpha) enhances X-ray killing of human tumor cells in vitro and enhances tumor control when combined with radiotherapy (RT) in animal tumor models. In multiple Phase I studies, intravenous injection of TNF-alpha appeared to have severe systemic side effects. To overcome these limitations, we used a bispecific antibody (BAb) directed against carcinoembryonic antigen and human TNF-alpha to target this cytokine in human digestive carcinoma treated with simultaneous RT. We used human digestive carcinoma cell lines (colon cancer, LS174T, and pancreatic cancer, BxPC-3) to determine the interaction of TNF-alpha and RT on clonogenic cytotoxicity. Isobolograms were established to confirm additive or supra-additive effects between both treatments. LS174T and BxPC-3 cells were grafted subcutaneously at Day 0 into female nude mice (7-8 weeks old). When the tumors reached a volume of about 80 mm(3), the mice were randomly assigned to treatment: Group 1, normal saline i.v. injection (control group); Group 2, TNF-alpha at 1 microg/i.v. injection; Group 3, BAb at 25 microg/i.v. injection; Group 4, BAb plus TNF-alpha (ratio 25 microg to 1 microg) i.v. injection; Group 5, local RT plus normal saline (0.5 Gy. min(-1)) at a total dose of 30 Gy delivered in five fractions; Group 6, local RT plus TNF-alpha injections 3 h before RT; Group 7, local RT plus BAb plus TNF-alpha co-injected 24 h before RT. Tumor growth delay was used as the end point for all groups. In the LS174T experiments, TNF-alpha added 12 h before RT showed a statistically significant decrease in the survival fraction at 2 Gy compared with RT alone (0.23 vs. 0.42 Gy, p = 0.0017). These results were largely confirmed with the BxPC-3 cell lines (0.29 vs. 0.72, p <0.00001). Isobolograms confirmed the additivity between TNF-alpha and RT in both cell lines. At 50% survival, the data points were within the envelope of additivity. In the LS174T and BxPC-3 xenografts, RT as a single agent (Group 5) slowed tumor progression compared with Group 1 (p <0.027 and p = 0.00001, respectively). TNF-alpha alone, BAb alone, or BAb plus TNF-alpha (Groups 2, 3, and 4) had no effect. In the LS174T model, TNF-alpha plus RT enhanced the delay to reach 2000 mm(3) compared with RT alone but without statistical significance. This delay was significantly longer when BAb was added (p = 0.0033, for Group 6 vs. Group 7). In the BxPC-3 experiments, the median delay to reach 2000 mm(3) was similar between the RT and TNF-alpha plus RT groups (93 days). The use of our BAb in combination with TNF-alpha and RT dramatically enhanced this median delay (177 days, p = 0.0013). No body weight loss was observed in any group. Our data could be used as a solid preclinical rationale on which to base a clinical study of locally advanced pancreatic or rectal cancers in the near future.
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PMID:A bispecific antibody to enhance radiotherapy by tumor necrosis factor-alpha in human CEA-expressing digestive tumors. 1475 31

In general a rising carcinoembryonic antigen (CEA) level means tumor progression. We observed a transient increase in CEA level despite objective response among patients receiving chemotherapy for metastatic colorectal cancer. This surge phenomenon has not previously been described for patients with metastatic colorectal disease. CEA was measured every second week in 27 patients receiving oxaliplatin, 5-fluororuracil, and folinic acid as first-line therapy against metastatic colorectal cancer. Four patients (15%, 95% CI 5-31%) met the criteria for therapy-induced CEA surge. The time of reaching maximum CEA level varied from 13 to 56 days. Median rise in CEA from baseline was 263% (range 24-632%). An initial rise of CEA during chemotherapy in colorectal cancer patients may therefore not always indicate progression of disease but may be a transient CEA surge in patients responding to chemotherapy.
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PMID:Transient CEA increase at start of oxaliplatin combination therapy for metastatic colorectal cancer. 1592 89

Serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and squamous cell carcinoma (SCC) antigen levels were assessed to determine if their levels are useful for staging esophageal cancer preoperatively and for predicting patient survival after esophagectomy. Hence their seropositivity was investigated for a correlation with resectability, clinicopathologic parameters of tumor progression, and treatment outcomes in patients with unresectable esophageal cancer ( n = 63) and those undergoing esophagectomy for resectable disease ( n = 267). Abnormal elevation of serum SCC antigen levels showed a significant correlation with resectability ( p< 0.0001), depth of tumor invasion ( p < 0.0001), lymph node status ( p = 0.0015), TNM stage ( p < 0.0001), lymphatic invasion ( p = 0.0019), blood vessel invasion ( p = 0.0079), and poor survival after esophagectomy ( p = 0.0061). A significant relation ( p = 0.0145) was found between elevated serum CEA levels and distant metastasis, whereas the seropositivity of CA 19-9 showed no association with resectability, tumor progression, or patient survival. These results indicate that abnormal elevation of serum SCC antigen is a useful predictor of advanced esophageal cancer associated with poor survival after esophagectomy.
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PMID:Clinical significance of serum carcinoembryonic antigen, carbohydrate antigen 19-9, and squamous cell carcinoma antigen levels in esophageal cancer patients. 1538 68


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