Cancer-associated fibroblasts induce cancer cell apoptosis that regulates invasion mode of tumours

Abstract

In the process of cancer spreading, different modes of invasion exist. One is expansive invasion, in which a group of cancer cells gradually expands along with cancer cell proliferation. Invasion of cancer cells is also modified by their interaction with stromal cells including cancer-associated fibroblasts (CAFs). Cancer cells co-invade with CAFs, and invasion by CAFs frequently precede invasion by cancer cells, which indicates CAF-led cancer cell invasion. Here, we show that CAFs induce apoptosis in gastric cancer cells, which prevented expansive invasion by cancer cells and instead facilitated CAF-led invasion. Death receptor 4 and activation of caspase-8 in cancer cells mediated cancer cell apoptosis induced by CAFs, which was dependent on contact between cancer cells and CAFs. Apoptotic cancer cells in turn released apoptotic vesicles and stimulated invasion of CAFs. Accordingly, cancer cells followed the migrating CAFs. Treatment with a caspase inhibitor, ZVAD, or forced expression of a death domain fragment in cancer cells prevented cancer cell apoptosis induced by CAFs and increased expansive invasion by cancer cells in extracellular gel invasion assays, while the rate of cancer cell invasion led by CAFs was decreased. Death domain-fragment expression also prevented intramural invasion by gastric cancer cells in the stomach. Because CAF-led invasion is characterized by the movement of individual cancer cells away from the tumour, adequate cancer cell apoptosis may promote cancer dissemination.

CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review

“…CTLs release TNF‐α to the TME for induction of apoptosis in cancer cells (Bourboulia & Stetler‐Stevenson, ). Cancer cell apoptosis, as it was discussed before, could stimulate CAF invasiveness through releasing apoptotic vesicles (Itoh et al, ). CAFs have multiple interactions with tumor promoter cells within the TME that would make therapeutic approaches more sophisticated.…”

The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development

“…Whilst still the topic of much debate as to the precise antitumourigenic and/or protumourigenic properties of this fibrotic reaction, it ultimately leads to a significantly altered tumour microenvironment both biochemically and biomechanically . The response is manifested by the presence of activated fibroblasts, either resident or recruited to the site of the developing tumour . These fibroblasts have been shown to be the major source of tumour desmoplasia, by secreting and remodelling ECM components including collagens.…”

“…These fibroblasts have been shown to be the major source of tumour desmoplasia, by secreting and remodelling ECM components including collagens. These cancer‐associated fibroblasts (CAFs) are now seen as critical in the progression of many solid tumours . Thus, given the critical importance of these stromal cells in tumour onset and progression, their inclusion in 3D cancer models is of utmost importance.…”

“…[27][28][29][30][31] The response is manifested by the presence of activated fibroblasts, either resident or recruited to the site of the developing tumour. 1,2,[32][33][34][35][36][37][38] These fibroblasts have been shown to be the major source of tumour desmoplasia, by secreting and remodelling ECM components including collagens. These cancer-associated fibroblasts (CAFs) are now seen as critical in the progression of many solid tumours.…”

Recent advances in understanding the complexities of metastasis

“…Cancer-associated fibroblasts (CAFs) have been shown to promote cancer cell invasion and metastasis 103 through a number of mechanisms, including exerting physical forces on cancer cells via heterotypic E-cadherin/N-cadherin adhesions that enable collective invasion 71 ( Figure 1i and Figure 2c). In addition, it is known that CAFs heavily influence cancer cell behaviour by inducing processes such as EMT to initiate their invasion 104– 107 or driving apoptosis to facilitate the switch between expansive invasion and CAF-led invasion 108 . Thus, the concept that tumours behave as communities 109 , in which cooperative behaviour occurs not only between cancer cell subclones but also between malignant and non-malignant cells 110 , adds significantly to the layers of complexity in treating these highly heterogeneous tumours.…”