Detection and prognostic impact of disseminated tumor cells in pancreatic carcinoma

Vogel, Ilka; Kalthoff, Holger; Henne‐Bruns, Doris; Kremer, Bernd

doi:10.1159/000055896

Cited by 26 publications

(26 citation statements)

References 69 publications

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“…We showed previously that nonadherent fibroblasts or tumor cell lines had diminished sensitivity to DNA damage (3). Although there is evidence that tumors in vivo shed large numbers of cells into the circulation (13)(14)(15)(16), matrix proteolysis and invasion by tumor cells may more commonly decrease adhesive strength without causing complete detachment (17). We therefore sought to test whether decreased levels of adhesion affected sensitivity to DNA damage.…”

Section: Resultsmentioning

confidence: 99%

Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl

Truong

Sun

Doorly

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Conventional cancer therapies are based on preferential killing of tumor cells by DNA damage. Previous work showed that, for certain cell types, loss of integrin-mediated adhesion decreased the apoptotic response to DNA damage because of decreased p53 levels after detachment from the extracellular matrix. Integrin ligation restored p53 and sensitivity to DNA damage. In this study, we show that c-Abl mediates a second pathway by which adhesion to extracellular matrix regulates cell killing by chemotherapeutic agents 5-arabinofuranosylcytosine, cisplatin, and camptothecin. Activation of c-Abl tyrosine kinase by DNA damage requires cell adhesion. Abl-dependent stabilization of p73, a p53-related proapoptotic transcription factor, is also adhesion-dependent. Sensitivity to the Abl inhibitor STI571 suggests differential utilization of the p53 and c-Abl͞p73 pathways by different tumor cell lines. These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl͞p73 pathway.C urrent cancer therapies are based primarily on radiation and chemotherapy that damage DNA to selectively kill fastgrowing tumor cells. This strategy is efficacious in the treatment of childhood leukemia and solid tumors at early stages, but suffers from the limitation that a small number of cancer cells commonly evade therapy and accumulate additional mutations, leading to recurrence of therapy-resistant tumors. The tumor suppressor gene p53 provides a key pathway that mediates cell death after DNA damage (1, 2). DNA damage increases the level and the transcriptional activity of p53, resulting in induction of cell cycle arrest genes such as p21 Waf1 and proapoptotic genes such as Noxa, Puma, and Bax. Inactivation of p53 is one of the most common genetic alterations in human cancer and is associated with progression to metastatic disease, resistance to therapy, and genomic instability.We recently described an effect of integrin-mediated adhesion on p53 levels and subsequent sensitivity of cells to DNA damage (3). For susceptible cell types, loss of adhesion to extracellular matrix (ECM) caused a decrease in p53 levels, leading to decreased apoptosis after exposure to ionizing radiation or chemotherapeutic drugs. The change in p53 was caused by a more rapid decline in levels of p19Arf, which inhibits MDM2 to prevent ubiquitin-and proteosome-dependent degradation of p53. This behavior was cell type specific. It was observed in a melanoma, a rhabdomyosarcoma and a fibrosarcoma line, as well as primary mouse embryonic fibroblasts (MEFs). However, several other tumor cell types either died directly after detachment or showed no decrease in sensitivity to DNA damage in suspension.A second pathway that mediates cellular responses to DNA damage involves the c-Abl tyrosine kinase. Activation of c-Abl by DNA damage contributes to cell cycle arrest and apoptosis via the p53 homolog p73 (4-6). Interestingly, c-Abl is also regulated by integrins (7,8). Detachment of cells from th...

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Section: Resultsmentioning

confidence: 99%

Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl

Truong

Sun

Doorly

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Additional to cytology, immunohistochemical analysis is the standard for identification of tumor cells. Despite improvement of detection rates by conventional cytology, conflicting result regarding the prognostic relevance have been reported [7] . Several studies focused on molecular biological approaches for the qualitative or semi-quantitative verification of tumor cell dissemination in pancreatic cancer [8][9][10][11][12] .…”

Section: Detection Of Disseminated Pancreatic Cells By Amplification mentioning

confidence: 99%

“…Several studies focused on molecular biological approaches for the qualitative or semi-quantitative verification of tumor cell dissemination in pancreatic cancer [8][9][10][11][12] . Reverse transcriptase polymerase chain reaction (RT-PCR) has a high sensitivity and allows the identification of approximately 1 tumor cell in 10 7 normal peripheral mononuclear blood cells [13] . Using qualitative PCR methods, varying frequency of gene transcripts and false positive results have been reported [14][15][16] .…”

Section: Detection Of Disseminated Pancreatic Cells By Amplification mentioning

confidence: 99%

Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients

Hoffmann¹

2007

WJG

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“…Possibly R-0 and R-1 resections are both accompanied by (occult) metastatic disease. Indeed, in an overview of advanced molecular detection techniques [6], it was shown that tumor cells can be found pre- and perioperatively in peritoneal lavage fluids, liver, blood, ‘tumor-negative’ lymph nodes, and bone marrow of patients without ‘conventional’ evidence of metastatic disease. As a result, R-0 resection offers an opportunity for long-term survival for a limited number of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Adjuvant chemotherapy and chemoradiotherapy after curative resection are of limited value [5]. Even after a macroscopically radical resection (R-0), distant micrometastases probably already exist [6], and tumor cells are often observed at one or more edges of the resected specimen (R-1) [7, 8]. Reported relevant prognostic variables for survival after resection are: tumor size, lymph node metastasis, histological differentiation, and resection status [9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Survival after Radical Resection for Pancreatic Head and Ampullary Cancer: A Potential Role for the EGF-R

Smeenk¹,

Erdmann²,

Dekken³

et al. 2007

Dig Surg

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Background/Aim: Pancreatic cancer has a dismal prognosis. Ampullary cancer (defined as cancer of the ampulla of Vater or the distal common bile duct) has a better prognosis and is thought to be a biologically different tumor. The aim of this study was to find factors that could predict survival after radical (R-0) resection for pancreatic head and ampullary cancers. Methods: We analyzed clinical and pathological data from 93 patients who underwent a true R-0 resection for pancreatic head or ampullary cancer. Furthermore, we performed a tissue microarray protein expression analysis for several growth factor receptors and oncogenes: HER-2, EGF-R, ER, PR, C-myc, p53, p16, RB-1, and chromogranin A as a neuroendocrine differentiation marker. Results: Median survival (14 vs. 42 months) and time to recurrence (16 vs. 42 months)were significantly longer for ampullary than for pancreatic head cancers. Preoperative pain, perineural invasion, lymph node metastasis, and tumor differentiation grade are indicators of a poor survival. No differences in protein expression were found between groups, except for EGF-R which was expressed more in pancreatic head cancers (p = 0.026). Conclusions: Outcomes for ampullary cancers are better than for pancreatic head cancers. This different biological behavior can possibly be explained by differences in EGF-R expression.

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Detection and prognostic impact of disseminated tumor cells in pancreatic carcinoma

Cited by 26 publications

References 69 publications

Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl

Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl

Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients

Long-Term Survival after Radical Resection for Pancreatic Head and Ampullary Cancer: A Potential Role for the EGF-R

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