Mechanisms of loss of HLA class I expression on colorectal tumor cells

Browning, Michael; Petronzelli, Fiorella; Bicknell, David; Krausa, P.; Rowan, Andrew; Tonks, Susan; Murray, Nick; Bodmer, J.; Bodmer, Walter F.

doi:10.1111/j.1399-0039.1996.tb02571.x

Cited by 93 publications

(51 citation statements)

References 35 publications

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“…(18,26,27) We and other investigators have demonstrated loss of HLA haplotype secondary to loss of heterozygosity mainly in cell lines and tissue sections from solid tumors. (22,(28)(29)(30)(31)(32)(33)(34)(35) We know of no report concerning HLA haplotype deletion in leukemic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Loss or down-regulation of HLA class I antigen expression has been demonstrated in a variety of tumors, and can have several causes: absence of β2M or transporter associated with antigen processing (TAP) expression; (17)(18)(19)(20) loss of heterozygosity, large deletions, or mitotic recombination in chromosome 6; (18,21,22) transcriptional down-regulation; (23)(24)(25) and point mutation, partial deletion, or somatic recombination. (18,26,27) We and other investigators have demonstrated loss of HLA haplotype secondary to loss of heterozygosity mainly in cell lines and tissue sections from solid tumors.…”

Section: Discussionmentioning

confidence: 99%

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Loss or down‐regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts

Masuda¹,

Hiraki

Fujii³

et al. 2006

Cancer Science

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Loss or down-regulation of human leukocyte antigen (HLA) class I expression has been demonstrated in a variety of solid tumors. To date, such altered HLA expression has not been studied extensively in freshly isolated leukemic blasts. If it occurs, leukemic cells could escape T-cell surveillance as a consequence. Genotypes of nine leukemic cell lines were determined using a polymerase chain reaction for HLA classes I and II. Cells were also examined for HLA β β β β2-microglobulin, and allele-specific HLA protein expression using flow cytometry. Next, 44 samples of freshly isolated leukemic blasts from 43 patients with malignant hematological diseases were examined for allele-specific HLA expression using flow cytometry.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Loss or down‐regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts

Masuda¹,

Hiraki

Fujii³

et al. 2006

Cancer Science

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“…Hypermethylation silences MLH1 expression and is frequently found with increasing age and in the proximal colon (Issa, 2000;Momparler and Bovenzi, 2000). A number of mechanisms other than ␤2m-expression defects are known that can account for down-regulation of HLA-I expression, such as genetic defects in the coding sequences of the HLA-I heavy chains (Jimenez et al, 1999;Koopman et al, 2000), regulatory defects (Browning et al, 1996), or defects in antigen processing and presentation, eg, in transporter associated with antigen processing. For instance, the latter were shown to account for a large proportion of HLA-I alterations in breast cancer (Kaklamanis et al, 1995), head and neck squamous cell carcinomas (Feenstra et al, 1999;Seliger et al, 1997), and 14% of colorectal carcinomas (Kaklamanis et al, 1994).…”

Section: Hla-i and Prognosis In Colorectal Cancermentioning

confidence: 99%

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Menon

Morreau

Tollenaar

et al. 2002

Laboratory Investigation

117

104

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SUMMARY:To evaluate the prognostic impact of human leukocyte antigen class I (HLA-I) expression on immune surveillance in colorectal cancer, we studied 88 curatively resected tumors for HLA-A and HLA-B/C expression and correlated these data to clinical and histopathological parameters. HLA-A was normal (all tumor cells had HLA expression) in 32%, reduced (HLA-negative and -positive tumor cells coexisted) in 56%, or absent (no tumor cells expressed HLA) in 12% of evaluable cases. HLA-B/C was normal in 47%, reduced in 47%, and absent in 7% of the cases. Considering both markers, total HLA-I expression was normal in 27%, reduced in 63%, absent in 7%, and could not be evaluated in 3% of the cases due to absent HLA-A expression in tumor and normal cells. Down-regulation of HLA-A expression significantly correlated with a lower tumor stage (p ϭ 0.005), mucinous tumors (p ϭ 0.05), a lower incidence of recurrences (p ϭ 0.03), and a longer disease-free survival (p ϭ 0.02). Down-regulation of HLA-B/C expression correlated with a lower tumor stage (p Ͻ 0.001) and a longer disease-free survival (p ϭ 0.04). In multivariate analysis, HLA-A down-regulation was the only prognostic factor correlated with a longer disease-free survival (p ϭ 0.02). Six tumors were negative for HLA-A and -B/C and did not recur during follow-up. Therefore, we analyzed microsatellite instability (MSI) in these cases. Three of these six tumors indeed showed down-regulation of MLH-1, MSH-2, or MSH-6, indicating a MSI-high phenotype. Beta-2-microglobulin protein expression was lost in five of six of the HLA-I-negative cases, but frame shift mutations in three repetitive sequences in ␤2-microglobulin were absent. In contrast, loss of MLH-1, MSH-2, and MSH-6-protein expression was only observed in two of nine matched controls with reduced or normal HLA-A and -B/C expression. Our data showed that HLA-I was down-regulated in 72% of colorectal cancers and provided independent prognostic information for a longer disease-free survival. The better prognosis may be caused by elimination of HLA-negative cells by natural killer cells or by an attenuated tumor aggressiveness, as is seen in tumors with a MSI-high phenotype. (Lab Invest 2002, 82:1725-1733.

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“…Development of the cytotoxic immune response depends on the expression of MHC class I molecules. These are shown to be down-regulated in human cancers [124] and in response to aberrant Wnt signalling [96], and may contribute to a tumour's ability to escape the host defences.…”

Section: The Wnt Signalling Pathway In Cancermentioning

confidence: 99%

Wnt signalling and the mechanistic basis of tumour development

Ilyas

2005

The Journal of Pathology

156

141

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Abnormalities in the Wnt signalling pathway are found in a wide range of cancers. The diverse origin of these malignancies implies that the contribution that disrupted Wnt signalling makes to tumourigenesis is not limited to specific tissue types and thus can be regarded as a step which is 'generic' to the process of carcinogenesis. In recent years, rapid progress has been made in the understanding of the Wnt signalling pathway, giving an insight into how inappropriate activation of this pathway may facilitate the neoplastic conversion of a normal cell. Furthermore, elucidation of the mechanisms that regulate Wnt signalling has led to the possibility of manipulating these mechanisms in order to downregulate Wnt signalling in established tumours. In this review, the Wnt signalling pathway is described. The role of aberrant Wnt signalling in tumour development is discussed together with its clinical implications for anti-tumour therapy.

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Mechanisms of loss of HLA class I expression on colorectal tumor cells

Cited by 93 publications

References 35 publications

Loss or down‐regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts

Loss or down‐regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts

Down-Regulation of HLA-A Expression Correlates with a Better Prognosis in Colorectal Cancer Patients

Wnt signalling and the mechanistic basis of tumour development

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