Tumor microenvironment pathways: Cross regulation in breast cancer metastasis

Abstract

The tumor microenvironment (TME) is heterogeneous and contains a multiple cell population with surrounded immune cells, which plays a major role in regulating metastasis. The multifunctional pathways, Hedgehog (Hh), Wnt, Notch, and NF-kB, cross-regulates metastasis in breast cancer. This review presents substantial evidence for cross-regulation of TME components and signaling pathways, which makes breast TME more heterogeneous and complex, promoting breast cancer progression and metastasis as a highly aggressive form. We discoursed the importance of stromal and immune cells as well as their crosstalk in bridging the metastasis. We also discussed the role of Hh and Notch pathways in the intervention between breast cancer cells and macrophages to support TME; Notch signaling in the bidirectional communication between cancer cells and components of TME; Wnt signal pathway in controlling the factors responsible for EMT and NF-κB pathway in the regulation of genes controlling the inflammatory response. We also present the role of exosomes and their miRNAs in the cross-regulation of TME cells as well as pathways in the reprogramming of breast TME to support metastasis. Finally, we examined and discussed the targeted small molecule inhibitors and natural compounds targeting developmental pathways and proposed small molecule natural compounds as potential therapeutics of TME based on the multitargeting ability. In conclusion, the understanding of the molecular basis of the cross-regulation of TME pathways and their inhibitors helps identify molecular targets for rational drug discovery to treat breast cancers.

Keywords: Breast cancer; Cross-regulation; Hedgehog; NF-κB; Notch; Tumor microenvironment; Wnt.

Figure 1

Role of major stromal and immune cells in shaping breast tumor microenvironment. Cancer associated fibroblasts (CAFs) promotes the growth and invasion of breast tumor cells by enhancing ECM remodeling in TME. Tumor associated osteoclasts and osteoblasts (TAOs) increase the metastatic behavior by supplying growth factors and cytokines. Tumor associated endothelial cells (TAEs) promotes invasion, metastasis and drug resistance by forming vasculature. Tumor associated macrophages (TAMs) activates the target genes associated with anti-tumor immune response and anti-inflammatory activity in response to cytokines. T-regulatory cells (Tregs) diminish T-cell immunity to tumour-associated antigens by expressing high levels of immune checkpoint molecules. Myeloid derived suppressive cells (MDSCs) induce infiltration and secretion of IL-6, which in turn trigger metastasis. Tumor associated neutrophils (TANs) promotes tumor growth, invasion and metastasis via proteolysis of ECM. Dendritic cells (DCs) recognize critical mediators of TME and promotes antitumor immunity.

Figure 2

Cross regulation of TME pathways. NF-kB signaling inhibits Wnt signaling, activate Notch signaling, overexpress Shh, reduces β-catenin activity in protective mechanism and stimulates β-catenin expression in oncogenic mechanism. Notch signaling pathway decreases Hh signaling, targets Wnt/β-catenin signaling, suppresses Wnt/β-catenin target genes and activates exosomal miRNA-223. Hes 1, a Notch protein suppresses GLI1 expression. Hh pathway regulates Jagged 2. Wnt pathway inhibits NF-kB activity, overexpress β-catenin, activates βTrCP expression and activates GLI1 via β-catenin. Exosomal miRNAs regulates Notch, Wnt and Hh signaling via GSK. Exosomal miRNA-146 activates NF-kB signaling via Notch.

Figure 3

Cyclopamine inhibits breast cancer by different mechanisms. Cyclopamine inhibits invasive ability of breast cancer cells by suppressing NF-kB, MMP-2 and MMP-9. It inhibits growth of ER-positive and -negative breast cancer cells by inducing cytotoxicity. It induces cell cycle arrest by modulating MAPK/ERK signaling, and apoptosis by binding to hydrophobic core of SMO and sensitizes breast cancer cells to paclitaxel. Co-delivery of cyclopamine with BSA nanoparticles reverses doxorubicin resistance in breast cancer and co-delivery with doxorubicin eradicates stem cells.

Figure 4

SMO inhibitors targets breast cancer progression. Vismodegib and Sonidegib inhibits breast cancer cell proliferation by targeting SMO. Itraconazole inhibits Hh pathway by targeting SMO and inhibits cell proliferation by reducing Hh activation. It reduces drug resistance by inhibiting P-glycoprotein and angiogenesis.

Figure 5

Small molecules inhibit Wnt pathway. Small molecules inhibit breast cancer growth by targeting Wnt pathway via promoting degradation of β-catenin. IWR1 inhibits Wnt pathway by stimulating the degradation of β-catenin via activating Axin 1 and XAV939 inhibits Wnt pathway by blocking the degradation of Axin 1. NSC668036 and FJ9 inhibits Wnt signaling pathway by targeting Dishevelled via binding with Fizzled receptor.

Figure 6

Gamma-secretase inhibitors inhibit Wnt and Notch pathways. Gamma-secretase inhibitors (GSIs) reduce breast cancer progression by targeting Wnt and Notch pathways. GSIs inhibits Notch signaling by preventing the release of Notch ICD via blocking the cleavage of Notch, and Wnt pathway by preventing the release of β-catenin via blocking the cleavage of E-cadherin and CD44 signaling by preventing the release of CD44 ICD via blocking the cleave of CD44 through targeting gamma-secretase.

Figure 7

Genistein inhibits breast cancer stem cells by targeting developmental pathways. Natural compound genistein suppresses breast cancer growth by targeting Hh pathway via reducing SMO and GLI1 expression, inactivates NF-kB pathway via targeting Akt, and Notch signaling by reducing the expression of Notch 1 expression and Wnt pathway by blocking Wnt expression.

Figure 8

Curcumin inhibits breast cancer stem cells by targeting developmental pathways. The natural compound curcumin inhibits breast cancer growth by targeting Notch pathway via downregulating Notch 1, Hh pathway via suppressing GLI expression, NF-kB pathway via inhibiting oncogenic activity and prevents Wnt signaling by downregulating β-catenin via stimulating GSKβ-3.

Figure 9

EGCG inhibits breast cancer stem cells by targeting developmental pathways. The natural compound epigallocatechin gallate (EGCG) targets Shh signaling by suppressing GLI1 expression and GLI1 activity, Notch pathway by inhibiting Notch 1 transcription, NF-kB pathway by inhibiting its activity and Wnt signaling by downregulating β-catenin.