Innate Immune Program in Formation of Tumor-Initiating Cells from Cells-of-Origin of Breast, Prostate, and Ovarian Cancers

SIMPLE SUMMARY: Tumor-initiating cells, also known as cancer stem cells, are a subset of cancer cells in a tumor that sustain the tumor and are often responsible for therapy resistance and relapse. Developmentally, they are evolved from the cellular origin of their corresponding cancer type and, as a result, may inherit some expression programs from the cellular origin. This review aims to summarize data from the literature showing that several hormone-related cancers (i.e., breast, prostate, and ovarian) have a preferred luminal progenitor origin. These luminal progenitors express a common innate immune program (e.g., Toll-like receptors and their associated genes). Tumor-initiating cells originated from such luminal progenitors may inherit this program, which may contribute to their formation via activation of Toll-like receptor pathways and crosstalk with immune cells (e.g., macrophages). We propose a potential strategy to eliminate such tumor-initiating cells by enhancing immunotherapy via further activation of their inherited innate immune pathways. ABSTRACT: Tumor-initiating cells (TICs), also known as cancer stem cells (CSCs), are cancer cells that can initiate a tumor, possess self-renewal capacity, and can contribute to tumor heterogeneity. TICs/CSCs are developed from their cells-of-origin. In breast, prostate, and ovarian cancers, progenitor cells for mammary alveolar cells, prostate luminal (secretory) cells, and fallopian tube secretory cells are the preferred cellular origins for their corresponding cancer types. These luminal progenitors (LPs) express common innate immune program (e.g., Toll-like receptor (TLR) signaling)-related genes. Microbes such as bacteria are now found in breast, prostate, and fallopian tube tissues and their corresponding cancer types, raising the possibility that their LPs may sense the presence of microbes and trigger their innate immune/TLR pathways, leading to an inflammatory microenvironment. Crosstalk between immune cells (e.g., macrophages) and affected epithelial cells (e.g., LPs) may eventually contribute to formation of TICs/CSCs from their corresponding LPs, in part via STAT3 and/or NFκB pathways. As such, TICs/CSCs can inherit expression of innate-immunity/TLR-pathway-related genes from their cells-of-origin; the innate immune program may also represent their unique vulnerability, which can be explored therapeutically (e.g., by enhancing immunotherapy via augmenting TLR signaling).