Development of arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic Acid/protein kinase D signaling 

Abstract

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 signaling pathway in combination with inhibition of CD36 function may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and eliminating CSCs.

PKD-1 Signaling Is Required for the Maintenance of CSCs with Epithelial-mesenchymal Plasticity in Pancreatic Neuroendocrine Tumors

“…In contrast, the glandular epithelial cells in normal pancreatic tissue expressed minimal levels of CD44 (Figure 1 A & B; Supplementary Figure 1). Similar to our previous study in ER-positive breast cancers [24], a subset of CD44 + CD45tumor cells detached from their nests and accumulated near the capillaries or around the α-SMA + arterioles, along with the presence of CD44 + and CD45 + lymphatic cells (Figure 1C).…”

“…CSCs are a subpopulation of cells within a tumor that are able to initiate tumors when propagated in animal models, sustain proliferation, and promote metastasis and therapeutic resistance [8,12,[34][35][36][37]. CSCs and aggressive cancer cells can be found in close proximity to blood vessels as the perivascular niche enables perfusion of oxygen and nutrients [24,38]. To determine the presence and distribution of stem-like cancer cells in pNETs, we stained tissue sections from human pNET patients with the CSC marker CD44, the pericyte/vascular marker smooth muscle-alpha actin (α-SMA), and the lymphatic cell marker CD45.…”

“…Lysophosphatidic acid (LPA), a lipid signaling mediator, activates PKD-1 and promotes tumor initiation, development of cancer stem-like features and metastasis [24,[39][40][41][42][43]. To further determine the role of PKD-1 pathway in CSC maintenance, we treated pNET cells with LPA.…”

“…Protein kinase D (PKD-1), a member of the serine/threonine kinase D family, is involved in the regulation of chromatin remodeling by modulating histone deacetylases [17,18]. PKD-1 also activates PI3K/Akt signaling and regulates Notch 1 signaling in several different cell types, including vascular endothelial cells and cancer cells [3,[19][20][21][22][23][24][25]. Among many biological outcomes of PKD-1 signaling are the increased angiogenesis and tumor progression [3,20].…”

“…PKD-1 signaling is known to promote CSC maintenance in some caners but has not been well explored in pNET CSCs. This pathway promotes stem-like features of cancer cells in estrogen positive breast cancers and regulates endothelial cell (EC) differentiation and arteriolar remodeling [18,[21][22][23][24]28]. We hypothesized that PKD-1 signaling regulates CSC maintenance in pNETs.…”