Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell–Mediated Lysis

Abstract Background Tumour budding (TB) is an adverse histological feature in many cancers. It is thought to represent epithelial-to-mesenchymal transition, a key step in the metastatic process. The role of TB in breast carcinoma (BC) remains unclear. Aim To investigate the relationship between TB and other histological and molecular features of BC. Method A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Cochran–Mantel–Haenszel method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS). Result Seven studies with a total of 1040 patients (high grade TB n=519, 49.9%; low grade TB n=521, 50.1%) were included. A moderate- to high-risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node involvement (OR 2.28, 95% c.i. 1.74 to 2.98, P<0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P<0.001). Regarding molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen- (OR 1.66, 95% c.i. 1.21 to 2.29, P=0.002) and progesterone-receptor positive (OR 1.68, 95% c.i. 1.10 to 2.59, P=0.02) tumours. In contrast triple negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P=0.0006). Conclusion High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC. Take-home message High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.

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Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma

Human Pathology ◽

10.1016/j.humpath.2010.12.007 ◽

2011 ◽

Vol 42 (10) ◽

pp. 1410-1419 ◽

Cited By ~ 13

Author(s):

Xin-Xin Wang ◽

Zhengmao Zhu ◽

Dan Su ◽

Ting Lei ◽

Xiao Wu ◽

...

Keyword(s):

Breast Carcinoma ◽

Tumor Suppressor ◽

Cell Motility ◽

Poor Prognosis ◽

Leucine Zipper ◽

Epithelial To Mesenchymal Transition ◽

Human Breast ◽

Down Regulation ◽

Mesenchymal Transition ◽

Putative Tumor Suppressor

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Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0830-3 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 11

Author(s):

Pedro Marques ◽

Sayka Barry ◽

Eivind Carlsen ◽

David Collier ◽

Amy Ronaldson ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Aggressive Behaviour ◽

Epithelial To Mesenchymal Transition ◽

Neuroendocrine Tumours ◽

Tumour Microenvironment ◽

Gh3 Cells ◽

Ki 67 ◽

Mesenchymal Transition ◽

Hla Dr

Abstract Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n = 5). In vitro tumour–macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p < 0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p = 0.005), but fewer neutrophils (p = 0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p = 0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with “deleterious immune phenotype” (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67 ≥ 3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p = 0.015) and area (p < 0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

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