Anoikis in cell fate, physiopathology, and therapeutic interventions

Abstract

The extracellular matrix (ECM) governs a wide spectrum of cellular fate processes, with a particular emphasis on anoikis, an integrin-dependent form of cell death. Currently, anoikis is defined as an intrinsic apoptosis. In contrast to traditional apoptosis and necroptosis, integrin correlates ECM signaling with intracellular signaling cascades, describing the full process of anoikis. However, anoikis is frequently overlooked in physiological and pathological processes as well as traditional in vitro research models. In this review, we summarized the role of anoikis in physiological and pathological processes, spanning embryonic development, organ development, tissue repair, inflammatory responses, cardiovascular diseases, tumor metastasis, and so on. Similarly, in the realm of stem cell research focused on the functional evolution of cells, anoikis offers a potential solution to various challenges, including in vitro cell culture models, stem cell therapy, cell transplantation, and engineering applications, which are largely based on the regulation of cell fate by anoikis. More importantly, the regulatory mechanisms of anoikis based on molecular processes and ECM signaling will provide new strategies for therapeutic interventions (drug therapy and cell-based therapy) in disease. In summary, this review provides a systematic elaboration of anoikis, thus shedding light on its future research.

Keywords: anoikis; cell death; circulating tumor cells; extracellular matrix; integrin; tumor metastasis.

FIGURE 1

Extracellular signal regulation and transformation applications of anoikis. Integrin transmits ECM signals including physical and chemical signals to regulate anoikis, thereby regulating cell fate and participating in physiopathological processes of the body, which is of great significance for therapeutic interventions.

FIGURE 2

The regulatory relationship between the integrin family and anoikis. The results and mechanisms of different integrin subunits and their dimers regulating anoikis are different.

FIGURE 3

Engineering applications of anoikis. Conventional cell in vitro culture systems, including primary cell extraction, culture, proliferation, passage, cryopreservation, recovery, and heredity, continue to be blocked by anoikis. Physical, chemical, and biological regulatory processes based on ECM can regulate cell fate by affecting integrin, which is of great value for stem cell‐based differentiation, transplantation, stem cell therapy, and other engineering applications.

FIGURE 4

Anoikis are involved throughout the life. Anoikis is involved in the process from implantation of the fertilized egg to embryonic development, tissues and organs development, homeostasis maintenance, pathological processes, and body aging. CTCs, circulating tumor cells.

FIGURE 5

Anoikis is a necessary and ongoing barrier to tumor metastasis (CTC distant metastasis). During the process of tumor cells escaping from primary tumor and entering the blood, anoikis occurs continuously. Only the CTCs that maintains anoikis resistance can complete distant metastasis and colonization.

FIGURE 6

Anoikis in therapeutic interventions. Some regulatory drugs based on anoikis and integrins show potential to intervene in drug therapy and cell‐based therapy, which is helpful in overcoming disease progression, tumor metastasis, drug resistance, and stem cell survival issues. Additionally, there are several molecular pathways, noncoding RNAs, epigenetic modifications, and ECM regulation processes that can affect anoikis, which are potential intervention strategies for anoikis. ECM, extracellular matrix.