Differential Expression of Proliferation-Associated Molecules in Individual Micrometastatic Carcinoma Cells

Pantel, Klaus; Schlimok, Günter; Braun, Stephan; Kutter, D; Lindemann, Fritz; Schäller, G.; Funke, I.; Izbicki, Jakob R.; Riethmüller, Gert

doi:10.1093/jnci/85.17.1419

Cited by 448 publications

(279 citation statements)

References 19 publications

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“…Previous studies by Pantel et al (1993), Braun et al (2001a) and Solomayer et al (2006), reported high rates of HER2 overexpression ranging from 60 to 100% of cases, analysed by immunocytochemistry only. These rates could therefore be explained by technical aspects, that is, excessively sensitive immunohistochemistry technique.…”

Section: Discussionmentioning

confidence: 91%

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

et al. 2007

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Discrepancies have been reported between HER2 status in primary breast cancer and micrometastatic cells in bone marrow. The aim of this study was to assess HER2 gene status in micrometastatic cells in bone marrow and corresponding primary tumour. Micrometastatic cells were detected in bone marrow aspirations in a prospective series of 27 breast cancer patients by immunocytochemistry (pancytokeratin antibody). HER2 status of micrometastatic cells was assessed by fluorescence in situ hybridisation (FISH), respectively in 24 out of 27. Primary tumour HER2 status was assessed by immunohistochemistry (CB11 antibody) and by FISH in 20 out of 27 of the cases. HER2 was amplified or overexpressed in five out of 27 (18.5%) primary tumours and in four out of 27 (15%) micrometastatic cells. In two cases, HER2 was overexpressed and amplified in primary tumour, but not in micrometastatic cells, whereas, in one case, HER2 presented a low amplification rate (six copies) in micrometastatic cells not found in the primary tumour. We demonstrated that negative and positive HER2 status remained, in the majority of the cases, stable between the bone marrow micrometastasis and the primary tumour. Therefore, the efficiency of anti-HER2 adjuvant therapy could be evaluated, in a clinical trial, by sequential detection of HER2-positive micrometastatic cells within the bone marrow, before and after treatment.

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Section: Discussionmentioning

confidence: 91%

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

et al. 2007

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“…However, the fate of disseminated cancer cells can be influenced by the qualitative properties of these cells and by several host factors (Heiss et al, 1995a). Studies on disseminated tumour cells in bone marrow offer the possibility of investigating the penultimate step in the development of metastasis and to gain information about the induction and regulation of the ensuing growth (Frassica and Sim, 1988;Pantel et al, 1993;Diel et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Pantel et al (1993) investigated the expression of Ki-67, p120 and ErbB2 on micrometastatic breast and gastric cancer cells. They found a high incidence of ErbB2 expression on disseminated breast cancer cells in patients with metastasis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer

Solomayer

Diel²,

Wallwiener³

et al. 1997

Br J Cancer

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SummaryPatients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12 -a tumour-associated glycoprotein typically expressed by almost all breast cancer cells -and the anti-uPA antibody HD-UK9. Thirty-five of the 2E1 1-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPApositive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.

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“…Riesenberg et al (1993) detected PSA exclusively on disseminated prostate tumor cells and not in bone marrow cells, which are known to be PSA-negative. The proliferation antigen Ki67 is known to be expressed in bone marrow (Gerdes et al 1984), and Pantel et al (1993b) described positive Ki67 staining of CK18-positive as well as surrounding CK18-negative bone marrow cells. In contrast, the same study did not detect immunogold staining of bone marrow cells for p120, a proliferation marker that is absent in bone marrow (Pantel et al 1993b).…”

Section: Discussionmentioning

confidence: 99%

“…uPA-R as a central representative of the urokinase system, a pattern of factors known to be involved in tumor-associated proteolysis and potentially to represent a tumor cell's invasive capacity (Blasi 1993;Moller 1993), may indicate aggressive phenotypes of disseminated tumor cells. Other parameters also, such as the tyrosin kinase receptor Erb-B2 (Pantel et al 1993b) which is potentially associated with aggressive tumor cell growth, proliferation antigens (Pantel et al 1993b), or tissuespecific antigens such as prostate-specific antigen (PSA) (Riesenberg et al 1993), have already been identified on CK18-positive cells in bone marrow and may help in estimating their biological properties and tumor cell identity.…”

mentioning

confidence: 99%

Immunocytochemical Phenotyping of Disseminated Tumor Cells in Bone Marrow by uPA Receptor and CK18: Investigation of Sensitivity and Specificity of an Immunogold/Alkaline Phosphatase Double Staining Protocol

Allgayer

Heiss

Riesenberg

et al. 1997

J Histochem Cytochem.

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SUMMARYPhenotyping of cytokeratin (CK)18-positive cells in bone marrow is gaining increasing importance for future prognostic screening of carcinoma patients. Urokinase-type plasminogen activator receptor (uPA-R) is one example of a potential aggressive marker for those cells. However, a valid and reliable double staining method is needed. Using monoclonal antibodies against uPA-R and CK18, we modified an immunogold/alkaline phosphatase double staining protocol. UPA-R/CK18-positive tumor cell controls exhibited black uPA-R staining in 15-80% of cases and red CK18 staining in almost 100% of tumor cells. Isotype-and cross-matched controls were completely negative. Bone marrow from healthy donors was always CK18-negative. Reproducibility of CK18-positive cell detection was estimated in a series of specimens from 61 gastric cancer patients comparatively stained with the single alkaline phosphatase-anti-alkaline phosphatase (APAAP) and our double staining method (10 6 bone marrow cells/patient). In four cases, double staining could not reproduce CK18-positive cells. In 34 cases it revealed fewer or equal numbers, and in 23 cases more CK18-positive cells than the APAAP method. Overall quantitative analysis of detected cell numbers (838 in APAAP, range 1-280 in 10 6 ; double staining 808, range 0-253) demonstrated relative reproducibility of APAAP results by double staining of 97%. Correlation of results between both methods was significant ( p Ͻ 0.001, linear regression). Sensitivity of double staining tested in logarithmic tumor cell dilutions was one CK18-positive cell in 300,000. Specific uPA-R staining was seen on CK18-positive cells in bone marrow from 29 of 61 patients, and also on single surrounding bone marrow cells. To test the specificity of this staining, bone marrow cytospins from 10 patients without tumor disease were stained for uPA-R with the APAAP method. uPA-R expression was confirmed in all 10 cases, with a mean of 6.5% uPA-R-positive cells in 1000 bone marrow cells (SEM 1.2%). These results suggest that our double staining protocol is a sensitive, reproducible, and specific method for routine uPA-R phenotyping of disseminated CK18-positive cells in bone marrow of carcinoma patients.

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Differential Expression of Proliferation-Associated Molecules in Individual Micrometastatic Carcinoma Cells

Abstract: Although support from clinical follow-up is still needed, this study demonstrates that, beyond the mere presence of micrometastatic cells in bone marrow, useful prognostic information can be obtained by analysis of additional cell growth markers.

Cited by 448 publications

References 19 publications

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer

Immunocytochemical Phenotyping of Disseminated Tumor Cells in Bone Marrow by uPA Receptor and CK18: Investigation of Sensitivity and Specificity of an Immunogold/Alkaline Phosphatase Double Staining Protocol

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