Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors?

Abstract

The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the “aggressiveness niche” and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche.

A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment

“…Moreover, the level of IL-1β secreted from the TNBC cell lines; MDA-MB-231 (MDA231) and MDA-MB-468 (MDA468) is 3-4 fold higher than that secreted from the non-TNBC/luminal A cell lines; MCF7 and T47D (not shown). IL-1β secretion decreased >50% upon IRIS silencing in MDA231 and MDA468 (red bars, Supplementary Figure 3 , left) [ 34 ], and increased ∼2 fold when IRIS was overexpressed in MCF7 and T47D (red bars, Supplementary Figure 3 , right) [ 35 ].…”

“…Noteworthy, activated AKT, ERK, or NF-κB activate HIF-1α signaling in TNBC cells, leading to IL-1β expression/secretion [ 34 ]. Together suggest IRISOE enhances production/secretion of IL-1β in TNBC tumor cells under normal/normoxic, as well as hypoxic (e.g., within the aggressiveness niche in IRISOE TNBC tumors [ 35 ]) conditions through stabilization of HIF-1α and/or activation of AKT, ERK and/or NF-κB signaling.…”

“…TNBC cells establish contact with MSCs within tumors using IL-1β [ 35 ]. Thus, whether IRISOE TNBC cells interact with MSCs through IL-1β was investigated.…”

Validation of Gene Profiles for Analysis of Regional Lymphatic Metastases in Head and Neck Squamous Cell Carcinoma

“…STAT3 overexpression in metastatic sites may restrain the immune responses to render an immunosuppressive environment (Punt et al, 2015). PECAM1 (CD31) makes up a large portion of cell intercellular junctions and loss of its function may disrupt cell adhesion (ElShamy et al, 2016). Interaction of hypoxia-surviving cells with the immunosuppressive environment influenced by newly recruited tumor-associated macrophages (TAMs), mesenchymal stromal cells (MSCs), and other types of immune cells most likely form and maintain a necrotic/hypoxic core called "aggressiveness niche" that will be the foster ground for cancer metastasis precursors (Johnson, 2001).…”

Potential targeting of B7‐H4 for the treatment of cancer

“…First, the intrinsic pathway linking inflammation and cancer includes genetic alterations that lead to inflammation and carcinogenesis. Second, the extrinsic pathway linking inflammation and cancer is characterized by microbial/viral infections or autoimmune diseases that trigger chronic inflammation within tissues that are thereby associated with the eventual development of cancer . In either case, both of these pathways activate pivotal transcription factors of inflammatory mediators (e.g.…”