Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem.

Jacob M Smigiel,Kelsey Polak,Benjamin L Bryson,Ilaria Tamagno,Sarah E Taylor,Mark W Jackson

doi:10.20517/2394-4722.2019.26

Jacob M Smigiel, Kelsey Polak + Show 4 more

Open Access

https://doi.org/10.20517/2394-4722.2019.26

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Abstract

As a field we have made tremendous strides in treating breast cancer, with a decline in the past 30 years of overall breast cancer mortality. However, this progress is met with little affect once the disease spreads beyond the primary site. With a 5-year survival rate of 22%, 10-year of 13%, for those patients with metastatic breast cancer (mBC), our ability to effectively treat wide spread disease is minimal. A major contributing factor to this ineffectiveness is the complex make-up, or heterogeneity, of the primary site. Within a primary tumor, secreted factors, malignant and pre-malignant epithelial cells, immune cells, stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells’ remarkable ability to undergo epithelial/non-cancer stem cell (CSC) to mesenchymal/CSC (E-M/CSC) plasticity. The enhanced invasion & motility, tumor-initiating potential, and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis. While most work trying to understand E-M/CSC plasticity has been done on malignant cells, recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process. Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor. Moreover, we will discuss how one may potentially target these populations, ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.

Highlights

THE MORTALITY OF METASTATIC BREAST CANCERBreast cancer (BC) is the most commonly diagnosed cancer among women, and the second leading cause of cancer related deaths in women[1]
Our understanding of the metastatic cascade has increased in recent years: cells must degrade the extracellular matrix (ECM) surrounding them, extravasate into the circulatory or lymphatic system and circulate throughout the body, intravasate into the new organ tissue, and regain their proliferative capacity[3,4,5]
After targeting paracrine Hh signaling in vivo, via two clinically available smoothened inhibitors (SMOi) Vismodegib and Sonidegib, Cazet et al.[215] observed a suppression of cancer cell plasticity and increased sensitivity to docetaxel

Summary

Introduction

THE MORTALITY OF METASTATIC BREAST CANCERBreast cancer (BC) is the most commonly diagnosed cancer among women, and the second leading cause of cancer related deaths in women[1]. Understanding how BC cells escape the primary tumor, spread to distant organs, initiate outgrowth at a distant site, and developing therapies to target those metastatic processes remains a significant clinical challenge. Recent evidence has demonstrated a remarkable ability of pre-malignant epithelial cells to take on a more invasive phenotype able to intravasate and disseminate to secondary sites following signaling cues from the TME[15,16].

Results

Conclusion