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

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).

Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression

“…PCSCs exhibit intrinsic resistance to treatments ( Lin et al, 2017 ), including endocrine therapy ( Germann et al, 2012 ; Alumkal et al, 2020 ; Xu et al, 2022 ), chemotherapy ( Domingo-Domenech et al, 2012 ; Lai et al, 2019 ; Li S. et al, 2020 ), radiotherapy ( Chang et al, 2013 ; Tsao et al, 2019 ), and immunotherapy ( Zhang et al, 2018a ; Han et al, 2023 ). For example, ABCG2+ PCSCs are resistant to androgen receptor inhibitors (ARIs) due to increased androgen efflux ( Huss et al, 2005 ).…”

“…Moreover, PCSCs engage in intricate interactions with cytokines, signaling molecules, the ECM, and other factors in the adjacent TME. Ecological niches protect PCSCs by maintaining and enhancing their stemness ( Chaves et al, 2021 ; Runcie and Dallos, 2021 ; Han et al, 2023 ). The TME is usually stable and not easily disturbed by external factors.…”