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Molecular Mechanisms of Hereditary Diffuse Gastric Cancer Initiation and Progression

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Spotlight on Familial and Hereditary Gastric Cancer

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Abstract

The stomachs of CDH1 germline mutation carriers contain multifocal, stage T1a signet ring cell carcinomas which are generally indolent, but show an unpredictable tendency towards rapid progression. The trigger for the initial development of these cancer foci is downregulation of the 2nd CDH1 allele, largely through epigenetic mechanisms. The loss of E-cadherin expression impacts on the orientation of the mitotic spindle, and we hypothesise that a proportion of proliferating cells in the gastric gland divide out of the epithelial plane and penetrate the lamina propria. It is possible that a proportion of the foci of signet ring cells in the lamina propria are transient, perhaps due to the absence of stem cell capability. Other foci in time undergo an epithelial-mesenchymal transition, in which they gain a more fibroblastic appearance, mediated at least in part by the expression of the oncogene c-SRC, and acquire the ability to invade surrounding tissues. In addition to highlighting the importance of an epithelial-mesenchymal transition, studies on sporadic disease suggest crucial roles for the Notch and Hedgehog pathways in disease progression. Deregulation of these pathways is likely to cooperate with E-cadherin downregulation to impact on fundamental biological processes including cellular interactions, differentiation and stemness.

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Abbreviations

CAF:

Cancer-Associated Fibroblasts

CSC:

Cancer Stem Cell

DGC:

Diffuse Gastric Cancers

EMT:

Epithelial-Mesenchymal Transition

HDACi:

Histone Deacetylase Inhibitors

HDGC:

Hereditary Diffuse Gastric Cancer

HH:

Hedgehog

LBC:

Lobular Breast Carcinomas

LCIS:

Lobular Carcinoma In Situ

LOH:

Loss Of Heterozygosity

MMP:

Matrix Metalloproteases

SRCC:

Signet Ring Cell Carcinoma

VPA:

Valproic Acid

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Authors and Affiliations

  1. Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, 9016, New Zealand

    Parry Guilford Ph.D.

  2. Hepatobiliary Laboratory, Department of Visceral and Transplantation Surgery, University Hospital Zurich, 8091, Zurich, Switzerland

    Bostjan Humar Ph.D.

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  1. Parry Guilford Ph.D.
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Correspondence to Parry Guilford Ph.D. .

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  1. Dept. of Medical, Surgical Sciences, and Neurosciences, University of Siena, viale Bracci, Siena, 53100, Italy

    Giovanni Corso

  2. Dept. of Medical, Surgical Sciences, and Neurosciences, University of Siena, Via Banchi di Sotto 55, Siena, 53100, Italy

    Franco Roviello

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Guilford, P., Humar, B. (2013). Molecular Mechanisms of Hereditary Diffuse Gastric Cancer Initiation and Progression. In: Corso, G., Roviello, F. (eds) Spotlight on Familial and Hereditary Gastric Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6570-2_6

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