Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients

Z’graggen, Kaspar; Centeno, Barbara A.; Castillo, Carlos Fernández‐del; Jimenez, Ramon E.; Werner, Jens; Warshaw, Andrew L.

doi:10.1067/msy.2001.113819

Cited by 86 publications

(63 citation statements)

References 42 publications

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“…Because circulating T cells may not be representative for lymphatic organs (which are sites for generation and storage of T cells), we also analyzed T cells from the bone marrow of pancreatic cancer patients. Bone marrow is an intriguing organ for T cell immunity because: (a) it is an organ for homing of blood-derived T cells and contains resident dendritic cells and monocytes/macrophages which can function as antigen-presenting cells (14)(15)(16); (b) it has been recently shown to be a site of naïve T cell priming and memory T cell generation against blood-borne tumor-associated antigens (14); (c) in breast cancer patients, bone marrow has been shown to be enriched with therapeutically relevant tumor-reactive memory T cells (17,18,24); (d) in pancreatic cancer, bone marrow is known to be a homing site for disseminated tumor cells (21,22); and (e) in comparison to tumor-draining lymph nodes, bone marrow is not so directly influenced by immunomodulatory factors from the tumor and may therefore allow polarization of TH1 responses.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in patients with breast cancer, multiple myeloma and malignant melanoma human bone marrow was found to contain large numbers of tumor-reactive memory T cells (17)(18)(19)(20). Pancreatic tumor cells have been detected in the blood and bone marrow of 24% to 34% of investigated patients (21,22) and might provide tumor antigens for induction or maintenance of local specific memory T cell responses.…”

Section: Introductionmentioning

confidence: 99%

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High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients

et al. 2005

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Pancreatic cancer is characterized by aggressive growth and treatment resistance. New approaches include immunotherapeutic strategies but the type and extent of spontaneous immune responses against tumor antigens remains unclear. A dominance of TH2 cytokines in patients' sera reported previously suggests systemic tumor-induced immunosuppression, potentially inhibiting the induction of tumor-reactive T cells. We characterized the localization, frequencies, and functional potential of spontaneously induced memory T cells specific for individual tumor antigens or the tumor-associated antigen mucin-1 in the peripheral blood and bone marrow of 41 pancreatic cancer patients. We found high numbers of tumor-reactive T cells in all bone marrow samples and in 50% of the blood samples. These cells secreted the TH1 cytokine IFN-; rather than TH2 cytokines upon stimulation with tumor antigens. Although consistently induced during pancreatic cancer, T cells specific for pancreatic antigens were not detected during chronic pancreatitis, suggesting that their evaluation may be of diagnostic use in both diseases. Freshly isolated T cells from cancer patients recognized autologous tumor cells and rejected them in vitro and in a xenotransplant model in vivo, suggesting their therapeutic potential. Thus, tumor antigen-specific T cell responses occur regularly during pancreatic cancer disease and lead to enrichment of tumor cell-reactive memory T cells in the bone marrow. The bone marrow can therefore be considered an important organ for antitumor immune responses in pancreatic cancer. (Cancer Res 2005; 65(21): 10079-87)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients

et al. 2005

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“…Therefore, the detection of these disseminated tumor cells (DTC) in distant organs such as the bone marrow (BM) could be important to identify patients at a high risk of disease progression and death and might indicate the need for further therapeutic approaches (2). Although significant associations with relapse and survival have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12), the prognostic relevance of the detection of BM-DTC in GI cancer patients is controversial (13)(14)(15). However, the biological characteristics and proliferative potential of this DTC are poorly understood (16).…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

Valladares‐Ayerbes

Blanco²,

Haz³

et al. 2011

Int J Oncol

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Abstract. The presence of tumor cells in the bone marrow (BM) could be relevant to identifying high risk of disease progression and death in gastrointestinal cancer. However, the molecular profile associated with disseminated tumor cells (DTCs) homing to the BM has yet to be defined. MicroRNAs (miRNA) play key roles in cellular processes implicated in cancer. Thus, we investigated in 38 patients with colorectal, gastric or pancreatic cancer whether the presence of BM-DTCs is associated with a specific miRNA tumor profile and analyzed their potential prognostic impact. DTCs were detected by immunocytochemistry and anti-cytokeratin antibodies in 42.1% of the patients. miRNAs were isolated from formalin-fixed, paraffin-embedded tumors. qRT-PCR was used for miRNA profiling. No significant associations were found among DTC detection and miRNA deregulation. Kaplan-Meier curves demonstrated significantly reduced progression-free survival (PFS) and overall survival (OS) in the DTC-positive patients. Although miR-21 was upregulated in 90.6% of the tumors, no associations with outcomes were found. miR-17 and miR-20a (miRNA-17-92 cluster) were upregulated in 33.3 and 42.4%, respectively. Upregulation of both was correlated and found in 30.3%. Univariate analysis shows that increasing values for miR-20a were significantly associated with reduced PFS (HR 1.022; p=0.016) and OS (HR 1.027; p=0.003). In multivariate Cox models, DTC positivity (HR 4.07; p=0.005) and miR-17 overexpression (HR 2.11; p=0.003) were significantly associated with a higher risk of disease progression. The presence of DTCs in the BM (HR 3.98; p=0.010) and a miR-17 overexpression (HR 2.62; p<0.001) were also associated with a risk of death. Our study suggests that the presence of BM-DTCs and the upregulation of the miR-17-92 cluster in tumors are both significant but independent prognostic markers in gastrointestinal cancer patients.

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“…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] . 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] .…”

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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Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients

Cited by 86 publications

References 42 publications

High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients

High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

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

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