Beta-catenin plays a central role in the ECD/catenin cell–cell adhesion complex, and it may be involved in cellular signaling pathways. Simultaneously, loss of E-cadherin and alpha-, beta-, and gamma-catenin are important steps in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Inactivation of E-cadherin through CDH1 gene mutation, loss of heterozygosity of chromosomal region 16q22.1, and/or gene promoter methylation is an early event reported in more than 95% of ILCs.22 Moreover, loss or downregulation of CDH1 is associated with tumor dedifferentiation and leads to different events: disruption of the tissue architecture, loss of adhesive properties and proliferation–suppressive function and gain in cellular motility increasing of invasive properties and dissemination of epithelial malignant cells. Of interest, ILC has been reported in families with hereditary diffuse gastric cancer that carry germline inactivation mutations of CDH1.23

From an immunohistochemistry point of view, ILCs are not positive for CK20 and express CK7, CK18, thrombospondin (TSP), and integrin alpha-V.31 ILC cells also express survivin, cathepsin B, TPI1, SPRY1, SCYA14, TFAP2B, osteopontin, HLA-G, and CHC1.


Continue Reading

With regard to genomic considerations, there are some genes overexpressed in ILCs that code proteins involved in cell adhesion like VWFELNDPT, and EMCN. There is upregulation of SFRP1,TGFBR2, and IGF1 genes. On the other hand, there are genes overexpressed in classic and pleomorphic ILCs implicated in actin cytoeskeleton remodeling/signaling and cell adhesion networks such as ANKDR28 and AFF1.21

It is worth mentioning the new role of chemokines in mechanisms of metastasization. Chemokines are a superfamily of chemotactic cytokines present in organs that act as specific modulators in leukocyte migration to sites of inflammation, but are also involved in the initiation and promotion of carcinogenesis by providing growth and angiogenic factors. There are two families that represent the bulk of known chemokines: CC (the first two cysteines are adjacent to one another) and CXC (the first two cysteines are separated by one amino acid).24

Chemokines interact with cell-surface receptors, present in tumor cells, which are members of a large superfamily of seven transmembrane G-protein-coupled cell surface receptors (GPCRs). Interaction between chemokines and their receptors induces migration of cells and mediates inflammatory and tumor cell migration. These chemokines stimulate certain cells to express their receptors by autocrine and paracrine mechanisms. More than 40 chemokines and 18 receptors are currently known.24

Chemokine receptors CXCR4 and CXCR7 are highly expressed in breast cancer cells, and they are responsible for the chemotaxis to certain target organs such as lymph nodes. CXCL12 (also named SDF-1alpha) and CCL21 (or 6Ckine) bind CXCR4 and CXCR7.25 The CXCL12/CXCR4 pathway is implicated in the mobilization, trafficking, and homing of cancer stem cells into metastatic sites.26

CXCR4 is implicated in vascularization by initiating and sustaining tumor formation. Signaling through chemokine receptors mediates actin polymerization and pseudopodia formation, favoring invasiveness. CXCR4 also stimulates the production of matrix metalloproteases.27

CXCL12 induces synthesis of metalloprotease MT1-MMP,27 modulates integrin expression, and promotes tumor cell adhesion by attaching cells to extracellular matrix proteins of the basement membrane or to ligands on other cells.28 CXCL12 can also regulate tumor cell apoptosis by activating NF-κB, which in turn inhibits tumor necrosis factor-α (TNF-α) production. Activation of NF-κB can sensitize cancer cells to CXCL12 stimulation through upregulation of CXCR4 expression. Methylation of CXCL12 promoter in the colonic epithelium favors metastases of tumors in the colon, but further studies are necessary to confirm this hypothesis. Breast tumor cells entering vascular or lymphatic circulation may migrate and adhere mainly to areas expressing CXCL12, therefore migrating to different organs.24

Carcinoma cells recruit normal fibroblasts into tumor masses. Fibroblasts produce growth factors, extracellular matrix molecules, and metalloproteases and secrete soluble factors with proinflammatory and suppressant effects. Fibroblasts activate and turn into carcinoma-associated fibroblasts (CAFs). These cells contribute to tumorigenesis and metastasis and are recruited by transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor (VEGF) released by tumor cells. In primary tumor and metastatic breast cancer, CAFs produce CXCL12 that promotes tumor growth and enhances angiogenesis through CXCR4 expressed on carcinoma cells and endothelial progenitor cells.29 Cytokines and chemokines derived from CAFs induce immune suppression and facilitate invasion and transendothelial migration. Interestingly, both stroma and cancer cells can produce CXCL12.

Furthermore, hypoxia induces CXCR4 expression and CXCL12 production, sensitizes tumor cells to CXCL12 signals, and promotes tumor metastasis.24,28 CXCL12 attracts vascular endothelial cells and plasmacytoid dendritic cells into the tumor environment, and these cells induce neoangiogenesis through production of IL-8 and TNF-β. CXCL12 expression seems to be regulated by hypoxia and a hormone-triggered signal pathway. The CXCL12/CXCR4-mediated tumor cell proliferation is regulated by estrogen signaling. In our case, the tumor expressed both ER and PR, which makes this pathway feasible.

It is known that interaction between CCL21 and CCR7 plays a crucial role in lymphocytes homing to secondary lymphoid organs through lymphatic vessels. The mechanism by which CCL21 mediates migration of tumor cells to lymph nodes is similar to the mechanism of the lymphocytes’ homing effect. This mechanism may underlie gastric metastasis in H. pylori gastritis by acting as an organ with a great inflammatory property similar to lymph nodes in our patient.