Blocking the Adhesion Cascade at the Premetastatic Niche for Prevention of Breast Cancer Metastasis

Abstract

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.

X-Aptamer Technology Identifies C4A and ApoB in Blood as Potential Markers for Schizophrenia

“…The aptamer technology has been most successfully applied in the field of cancer biology, where aptamers have been able to identify phenotypic variations between cell types, representing differences in molecular signatures [13,14]. We have shown that aptamers can safely target and reduce cancer metastasis [15][16][17], can be easily selected against tissues using a laser microdissection method [9], and enhance binding of liposomes and nanoparticles [17][18][19][20].…”

Lx2-32c–loaded polymeric micelles with small size for intravenous drug delivery and their inhibitory effect on tumor growth and metastasis in clinically associated 4T1 murine breast cancer

“…These results were consistent with a previous report that breast cancer could metastasize to distant organs through a hematogenous route. 29 Also, we found that inflammatory cell (neutrophils, yellow dotted circle) invasion was remarkable in the control group. As we know, inflammation is associated with cancer metastasis.…”

Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context

“…Filopodia then dynamically extends and retracts into the parenchyma as cells migrate to a perivascular position [46,48]. Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53] retracts into the parenchyma as cells migrate to a perivascular position [46,48]. Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53]).…”

“…Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53] retracts into the parenchyma as cells migrate to a perivascular position [46,48]. Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53]). The perivascular niche (PVN) is another critical point of tumour cell attrition-most are unable to tolerate the neuroinflammatory reaction that is rapidly instigated by microglia and astrocytes [28,45,48,[54][55][56][57][58][59][60][61].…”