Activation of Robo1 Signaling of Breast Cancer Cells by Slit2 from Stromal Fibroblast Restrains Tumorigenesis via Blocking PI3K/Akt/β-Catenin Pathway

Abstract

Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to down-regulation of c-myc and cyclin D1 via the PI3K pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in breast cancer patients, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and demonstrate that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.

Axon Guidance Factor SLIT2 Inhibits Neural Invasion and Metastasis in Pancreatic Cancer

“…These observations are in line with existing concepts on how loss of SLIT2 affects tumor progression, which propose that SLIT2 counteracts cell motility induced by chemoattractant stimulation via cytokines or growth factors (36)(37)(38). Different from the SLIT2 mode of action in breast (39) and lung cancer cells (40), we did not detect a SLIT2-dependent regulation of AKT activity in PDAC cells (data not shown), suggesting a cell type-specific wiring of downstream signals.…”

Favorable prognosis of operable non-small cell lung cancer (NSCLC) patients harboring an increased expression of tumor endothelial markers (TEMs)

“…Also in other tumor entities, e.g. breast and pancreatic cancer, it was recently shown that high Robo1 or Robo2 expression correlated with a more favorable prognosis [22,23]. Furthermore, it was shown that by applying recombinant Robo4 protein angiogenesis and/or tumor growth was inhibited, and vice versa that blocking Robo4 with monoclonal antibodies increased angiogenesis and disrupted vascular integrity [24].…”

New Antiangiogenic Strategies beyond Inhibition of Vascular Endothelial Growth Factor with Special Focus on Axon Guidance Molecules

“…Furthermore, in lung cancer, it was also reported that Slit2/Robo1 signaling suppresses lung cancer progression and that patients with loss of Slit2 had a poor prognosis [32]. Further data supported that inhibition of Robo1 signaling led to metastasis inhibition [31]. …”

“…Also, in other cancer entities, increased expression levels were of prognostic value, as seen in breast and pancreatic cancer [30,31]. Furthermore, in lung cancer, it was also reported that Slit2/Robo1 signaling suppresses lung cancer progression and that patients with loss of Slit2 had a poor prognosis [32].…”