Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated whether (a) carcinoembryonic antigen (CEA), cytokeratin-20 (CK-20) and guanylyl cyclase C (GCC) are clinically useful markers for the molecular detection of submicroscopic metastases in colorectal cancer (CRC) and (b) whether overexpression of CEA, CK-20 and GCC can be reliably detected in formalin-fixed, paraffin-embedded tissues as well as frozen lymph nodes. We studied 175 frozen lymph nodes and 158 formalin-fixed, paraffin-embedded lymph nodes from 28 cases of CRC. CEA or CK-20 or GCC-specific polymerase chain reaction (PCR) was carried out on mRNA transcripts extracted from the nodal tissues. Ten out of 11 Dukes' B CRC cases had detectable CEA and CK-20 while 6 out of 11 Dukes' B CRC cases had detectable GCC. In general, the difference of re-staged cases when comparing frozen and paraffin-embedded samples was marked; the only statistically significant correlation between frozen and paraffin tissue was for the CEA marker. Our results indicated a high incidence (>50%) of detecting micrometastases in histologically-negative lymph nodes at the molecular level.
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PMID:Intrinsic variability in the detection of micrometastases in lymph nodes for re-staging of colorectal cancer. effect of individual markers and tissue samples. 1276 11

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain. A third analogue, DOTA-11AUN-F19-STh(1-19), differs from the first in that it incorporates an 11-aminoundecanoic acid spacer group between the DOTA group and the first asparagine residue. In vitro competitive binding assays utilizing T-84 human colon cancer cells demonstrated that significant alterations to the N-terminal region of the STh molecule were well tolerated and did not significantly affect binding affinity of STh for the guanylyl cyclase C (GC-C) receptor. Internalization and efflux studies of the indium-labeled species demonstrated that inclusion of positive charge in the linker moiety inhibits internalization of the compound within tumor cells. The characteristics of the three analogues were compared in an in vivo model utilizing T-84 human colon cancer cell xenografts in SCID mice. Clearance of all analogues was rapid, primarily via renal excretion into the urine, with >89% ID excreted into the urine at 1 h pi for all analogues. The 111In-DOTA-R1,4,F19-STh(1-19) and 111In-DOTA-11AUN-F19-STh(1-19) analogues both had longer residence times in the blood than did the 111In-DOTA-F19-STh(1-19) analogue, probably accounting for increased %ID/g values for tumors and nontarget tissues at 1 h pi. At 4 h pi, significant differences between analogues were only seen with respect to metabolic routes of excretion, indicating that increased blood residence time did not result in increased tumor residualization. Reduction of hepatic uptake of these compounds, however, could have significance in the development of agents for the imaging of hepatic metastases. The ability to manipulate in vivo pharmacodynamics and tumor uptake of radiolabeled STh peptides through modification of linker moieties is under continuing investigation in order to produce optimal imaging and therapeutic radiopharmaceuticals.
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PMID:In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties. 1526 76

Colorectal cancer is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. While surgery remains the mainstay of therapy, approximately 50% of patients who undergo resection develop parenchymal metastatic disease. Unfortunately, current therapeutic regimens offer little improvement to the survival of patients with parenchymal metastases in the liver and lung. In that context, there is a significant unrealized opportunity at the intersection of engineering and biology for the development of novel targeted therapeutic approaches to colorectal cancer metastases. This opportunity exploits the discovery that an intestinal receptor, guanylyl cyclase C, which mediates diarrhea induced by bacterial heat-stable enterotoxins (STs), is over-expressed by metastatic colorectal tumors only. Moreover, it leverages recent advances in the fabrication of metal nanoshells with defined thicknesses absorb near-infrared (NIR) light, resulting in resonance and transfer of thermal energies of more than 40 degrees C. Thus, the conjugation of ST to gold nanoshells, which can undergo resonance excitation by NIR light and emit heat, represents a previously unrecognized approach for the targeted therapy of parenchymal colorectal cancer metastases, specifically to the liver and lung. This article discusses the potential of ST-targeted nanoshells for NIR thermal ablation of metastatic colorectal tumors and highlights the significant challenges and solutions linked to the translation of this emerging technology to patient care.
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PMID:Opportunities for near-infrared thermal ablation of colorectal metastases by guanylyl cyclase C-targeted gold nanoshells. 1715 97

Circulating tumor cell (CTC) detection in peripheral blood of colon and other epithelial cancer patients is becoming a scientifically recognised indicator for the presence of primary tumors and/or metastasis. The resulting need to further develop CTC detection-based systems for improved diagnosis, prognosis and assessment of therapy efficacy in tumour patients has prompted the application of different approaches, including expression analysis of tissue-specific and epithelial genes. In this context, lack of specificity of the analysed genes remains a fundamental problem for reliable CTC detection. In this study, we have selected a panel of highly specific epithelial genes: cytokeratin 20 (CK20), cytokeratin 19 (CK19), carcinoembryonic antigen (CEA) and guanylyl cyclase C (GCC), and performed RT-PCR analysis to assess their expression in total blood and in different cell fractions of peripheral blood (PBMC and CD45-negative population) of cancer patients and healthy controls. Our results demonstrate that analysis of a single gene in a CTC-enriched population (CD45(-) peripheral blood cells) of cancer patients allows detection of a CTC molecular signature in at most 63.3% of cases, while analysis of all four genes performed in all three sample types increases the detection of positive patient samples to 87.7%. Healthy controls did not show positivity for any combination of these genes, although positivity was observed for the CEA marker alone, which was detected in 3 (6.6%) out of 45 donors, and only in the CD45(-) fraction. Here, we demonstrate that combined analysis of the genes above, in multiple blood fractions, results in a highly specific and sensitive CTC detection system in patients with metastatic solid tumors. Therefore, we believe that validation on a large scale of this approach, which demonstrates higher specificity in patients compared to controls, could become a relevant CTC screening test in patients with established metastatic disease, and furthermore, may also be useful for evaluating the possible presence of CTCs before the onset of clinically manifested metastatic spreading.
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PMID:Molecular signature detection of circulating tumor cells using a panel of selected genes. 1826 45

The presence of tumor cells in regional lymph nodes is the most important prognostic and predictive marker in staging patients with colorectal cancer. Cancer cells in lymph nodes are associated with a poorer prognosis and an increased risk of recurrent disease. Additionally, nodal metastases identify patients who derive maximum benefit from adjuvant therapy. However, traditional paradigms for staging patients with colorectal cancer underestimate the extent of metastases and patients whose lymph nodes are ostensibly free of tumor cells by histopathology (pN0) have a 25-30% risk of developing recurrent disease, reflected by the presence of occult nodal metastases. These observations underscore the unmet clinical need for molecular approaches to accurately detect metastatic disease and identify patients at risk for disease relapse that could benefit from adjuvant chemotherapy. Detection of disease-specific mRNA targets as prognostic and predictive markers employing quantitative reverse transcription (qRT)-PCR is an emerging technology that has become a benchmark for individualization of patient management. However, to date, applications of qRT-PCR to detecting occult nodal metastases in colorectal cancer have been equivocal, reflecting markers with suboptimal sensitivity and specificity; limitations of utilizing qualitative, rather than quantitative, RT-PCR; and underpowered study designs based on inadequate patient populations. In that context, guanylyl cyclase C (GCC) is the most sensitive and specific biomarker for metastatic colorectal cancer in extra-intestinal tissues. GCC qRT-PCR detects occult metastases in lymph nodes, providing the most powerful independent prognostic information for predicting disease recurrence in pN0 patients in prospective multicenter clinical trials. This technology forms the basis for the Previstagetrade mark GCC Colorectal Cancer Staging Test encompassing a proprietary multiplex qRT-PCR assay compatible with formalin-fixed, paraffin-embedded lymph nodes for detecting occult metastases. Previstage GCC is a new diagnostic tool that may improve the accuracy of staging, prognosis of clinical outcomes and prediction of therapeutic responses to adjuvant therapy, representing a key advance in the management of patients with colorectal cancer.
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PMID:Previstage GCC test for staging patients with colorectal cancer. 1878 5

Matrix metalloproteinase-9 (MMP-9) produced by colorectal cancer cells is a critical determinant of metastatic disease progression and an attractive target for antimetastatic strategies to reduce colon cancer mortality. Cellular signaling by cyclic GMP (cGMP) regulates MMP-9 dynamics in various cell systems, and the bacterial enterotoxin receptor guanylyl cyclase C (GCC), the principle source of cGMP in colonocytes, which is overexpressed in colorectal cancers, inhibits tumor initiation and progression in the intestine. Here, we show that ligand-dependent GCC signaling through cGMP induces functional remodeling of cancer cell MMP-9 reflected by a compartmental redistribution of this gelatinase, in which intracellular retention resulted in reciprocal extracellular depletion. Functional remodeling of MMP-9 by GCC signaling reduced the ability of colon cancer cells to degrade matrix components, organize the actin cytoskeleton to form locomotory organelles and spread, and hematogenously seed distant organs. Of significance, GCC effects on cancer cell MMP-9 prevented establishment of metastatic colonies by colorectal cancer cells in the mouse peritoneum in vivo. Because endogenous hormones for GCC are uniformly deficient in intestinal tumors, reactivation of dormant GCC signaling with exogenous administration of GCC agonists may represent a specific intervention to target MMP-9 functions in colon cancer cells. The notion that GCC-mediated regulation of cancer cell MMP-9 disrupts metastasis, in turn, underscores the unexplored utility of GCC hormone replacement therapy in the chemoprevention of colorectal cancer progression.
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PMID:Guanylyl cyclase C prevents colon cancer metastasis by regulating tumor epithelial cell matrix metalloproteinase-9. 1933 67

Colorectal cancer (CRC) is the third most common cancer and a leading cause of death for both men and women in North America. The staging of the CRC at the time of diagnosis is the single most important prognostic factor in determining recurrence and survival. Until 2008, accurate evaluation of CRC stages I and II was based on examination of regional lymph nodes (LNs) under a microscope to identify cancer cells. This method can detect one cancer cell in 200 normal cells, but analyzes only a fraction of the available tissue from the LN (less than 0.1%). Up to 30% of patients assessed by traditional histopathology methods as having stage II disease (negative LNs) experience a recurrence of their cancer. Previstage GCC Colorectal Cancer Staging Test, a new molecular diagnostic test, is able to identify patients at high risk of recurrence by examining their LNs for guanylyl cyclase C (GCC). GCC is a marker found in cells lining the lumen of the gastrointestinal tract. The expression of GCC is conserved in CRC and metastatic disease. Using an ultrasensitive quantitative reverse transcription (RT)-PCR, the test interrogates a patient's LN tissues to identify GCC levels consistent with metastatic (stage III) disease. The technology employed in Previstage GCC is nearly 100,000 times more sensitive than microscopic staging methods. This molecular diagnostic test allows a more thorough examination of LNs and has an analytic sensitivity of 92% and a specificity of 98%. Such a test can be used to overcome the limitations of staging by traditional histopathology alone.
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PMID:Previstage GCC colorectal cancer staging test: a new molecular test to identify lymph node metastases and provide more accurate information about the stage of patients with colorectal cancer. 1935 Dec 10

Cancer mucosa antigens are emerging as a new category of self-antigens expressed normally in immunologically privileged mucosal compartments and universally by their derivative tumors. These antigens leverage the established immunologic partitioning of systemic and mucosal compartments, limiting tolerance opposing systemic antitumor efficacy. An unresolved issue surrounding self-antigens as immunotherapeutic targets is autoimmunity following systemic immunization. In the context of cancer mucosa antigens, immune effectors to self-antigens risk amplifying mucosal inflammatory disease promoting carcinogenesis. Here, we examined the relationship between immunotherapy for systemic colon cancer metastases targeting the intestinal cancer mucosa antigen guanylyl cyclase C (GCC) and its effect on inflammatory bowel disease and carcinogenesis in mice. Immunization with GCC-expressing viral vectors opposed nascent tumor growth in mouse models of pulmonary metastasis, reflecting systemic lineage-specific tolerance characterized by CD8(+), but not CD4(+), T-cell or antibody responses. Responses protecting against systemic metastases spared intestinal epithelium from autoimmunity, and systemic GCC immunity did not amplify chemically induced inflammatory bowel disease. Moreover, GCC immunization failed to promote intestinal carcinogenesis induced by germ-line mutations or chronic inflammation. The established role of CD8(+) T cells in antitumor efficacy, but CD4(+) T cells in autoimmunity, suggests that lineage-specific responses to GCC are particularly advantageous to protect against systemic metastases without mucosal inflammation. These observations support the utility of GCC-targeted immunotherapy in patients at risk for systemic metastases, including those with inflammatory bowel disease, hereditary colorectal cancer syndromes, and sporadic colorectal cancer.
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PMID:Lineage-specific T-cell responses to cancer mucosa antigen oppose systemic metastases without mucosal inflammatory disease. 1935 47

Rapidly growing insight into the molecular biology of colorectal cancer has led to high hopes for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on gene-specific biomarkers are contradictory in their findings, and no tests are currently used in clinical practice, with the exception of microsatellite instability (MSI) and guanylyl cyclase C (GCC) testing in the adjuvant setting, and in Europe KRAS mutation testing is used in the setting of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease. There are many reasons for the failure of the initial marker hypothesis-driven approach. Although supported by a good biologic rationale, single markers such as tumor protein p53 (TP53) gene mutations, when applied to a complex tumor type containing many synchronous alterations, do not perform well in predicting outcome. Many markers also suffer from technical shortcomings, resulting from the lack of quantitative techniques to capture the impact of the molecular alteration. The impact of markers obtained from microarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in the KRAS gene were shown to be strong negative predictors of response to EGFR inhibitors in metastatic disease. It has also been suggested that BRAF gene mutations may be predictive of EGFR inhibitor resistance, and there are some conflicting data regarding the role of the PIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine.
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PMID:Clinical biomarkers in oncology: focus on colorectal cancer. 1953 45

Colorectal cancer is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. While surgery remains the mainstay of therapy, approximately 50% of persons who undergo resection develop parenchymal metastatic disease. Unfortunately, current therapeutic regimens offer little improvement in survival. Using immunotherapy to fill this therapeutic gap has enjoyed limited success, reflecting a paucity of tumor-associated antigens. In that context, there is a significant unrealized opportunity to exploit structural and functional immune system compartmentalization to generate a therapeutic immune response against metastatic colorectal tumors employing biomarkers whose expression is normally confined to intestinal epithelial cells and their derivative malignancies. This novel class of biomarkers, here termed cancer mucosa antigens, may fill the unmet therapeutic need for colorectal cancer-associated immune targets. As a concrete example, guanylyl cyclase C is an intestinal mucosa-specific biomarker ideally suited to test this hypothesis and serve as the first cancer mucosa antigen for colorectal cancer immunotherapy. Here, we discuss colorectal cancer immunity, immune compartmentalization and preliminary results targeting guanylyl cyclase C in mouse models of colorectal cancer, as well as the potential paradigm shift to employing cancer mucosa antigens in immunotherapy of colorectal cancer.
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PMID:Mucosally restricted antigens as novel immunological targets for antitumor therapy. 2047 68


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