1. Introduction

Derived from the Greek word "anoikos," signifying homelessness ^[1], Anoikis holds a prominent place in cellular biology. It represents a programmed cell death mechanism that unfolds when cells lose their anchorage by detaching from their extracellular matrix (ECM) or surrounding tissue. Anoikis serves as a guardian of tissue homeostasis, orchestrating the elimination of potentially harmful detached cells. Beyond this critical role in normal physiology, anoikis is deeply intertwined with cancer biology, metastasis, and tissue regeneration ^[1]. This research embarks on a journey through the intricate molecular mechanisms governing anoikis, shedding light on its significance in maintaining the equilibrium of normal bodily functions. Moreover, we delve into the disruptive forces at play in cancer, where anoikis dysregulation becomes a harbinger of disease progression, fueling metastasis, therapy resistance, and unchecked tumor growth. In the quest for novel therapeutic strategies, the researchers explore the promising realm of targeting anoikis resistance, offering renewed hope to those battling cancer and the scientific community dedicated to combating this relentless adversary.

2. Molecular Mechanisms of Anoikis

Anoikis is orchestrated by a complex network of signaling pathways and molecular events that converge to trigger programmed cell death. Key mechanisms include the activation of death receptors, such as Fas and TNF receptor, in detached cells, leading to the initiation of apoptotic cascades mediated by caspases ^[2]. Additionally, the balance between pro-apoptotic (e.g., Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-xL) Bcl-2 family proteins plays a central role in anoikis, with detached cells experiencing a shift in this balance towards pro-apoptotic factors, promoting apoptosis ^[3]. Furthermore, integrins, critical transmembrane receptors facilitating cell-ECM interactions, become disrupted upon loss of attachment, resulting in decreased activation of FAK and downstream signaling events that favor cell survival. Lastly, anoikis often involves mitochondrial dysfunction, marked by increased permeabilization, cytochrome c release, and activation of the intrinsic apoptotic pathway, serving as a pivotal step in the execution of this programmed cell death process ^[4].

3. Anoikis in Normal Physiology

Anoikis assumes a multifaceted role in preserving tissue integrity, development, and regeneration within normal physiology. During embryonic development, it serves as an essential sculptor, eliminating cells that fail to integrate correctly into evolving tissues, thereby ensuring the precise formation of embryonic structures ^[5][6]. Throughout an organism's life, anoikis maintains tissue homeostasis by vigilantly removing damaged or senescent cells, preventing the accumulation of potentially harmful ones ^[7]. Following injuries, anoikis plays a crucial role in tissue regeneration, effectively clearing damaged cells to make way for the proliferation of healthy ones. Additionally, anoikis serves as a sentinel of immune surveillance, preventing the dissemination of detached cells, including potentially cancerous ones, thereby contributing to the body's defense against the development of malignancies ^[7][6].

4. Dysregulation of Anoikis in Cancer

The phenomenon of anoikis evasion by cancer cells stands as a defining and multifaceted characteristic of cancer progression, intricately woven into the fabric of several critical aspects of malignancy ^[8]. This remarkable ability to resist cell death induced by detachment from the extracellular matrix (ECM) is a pivotal contributor to the complex journey of cancer ^[9]. Firstly, anoikis resistance empowers cancer cells to overcome the formidable challenges posed by metastasis ^[9]. These cells, equipped with the capacity to endure in the bloodstream, find their way to distant organs, where they establish colonies, thus propelling the relentless spread of the disease. Moreover, cancer cells armed with anoikis resistance exhibit enhanced invasive capabilities, breaching the confines of their primary tumor and infiltrating neighboring tissues ^[10]. This invasive potential fuels the local expansion of the tumor, driving its progression. Importantly, the resilience of these cells extends to the realm of therapeutic interventions. Anoikis-resistant cancer cells demonstrate remarkable survival in the face of conventional treatments, such as chemotherapy and radiation therapy, thereby contributing significantly to therapy resistance and posing a formidable challenge in clinical management ^[7]. Additionally, anoikis evasion contributes to the sustenance and proliferation of cancer stem cells, a subgroup with heightened tumorigenic potential. This further amplifies tumor growth, underscoring the pivotal role of anoikis resistance in the relentless progression of malignancies. Consequently, comprehending and targeting this crucial aspect of cancer biology hold immense promise for developing innovative therapeutic strategies aimed at curbing metastasis, overcoming therapy resistance, and ultimately improving outcomes for cancer patients.

5. Mechanisms of Anoikis Resistance in Cancer

Comprehending the mechanisms underlying cancer cells' evasion of anoikis is paramount for the development of targeted therapeutic interventions. Several key mechanisms are involved in this process, offering potential targets for intervention. Alterations in apoptotic pathways are a common strategy employed by cancer cells, often exhibiting disrupted expression of Bcl-2 family proteins, resulting in an imbalance favoring anti-apoptotic factors, thus impeding anoikis ^[11]. Additionally, the activation of pro-survival signaling pathways, such as PI3K/Akt and ERK/MAPK, plays a pivotal role in protecting cancer cells from anoikis-induced death ^[12]. Epithelial-Mesenchymal Transition (EMT) enables cancer cells to acquire a more invasive phenotype while concurrently developing resistance to anoikis. Furthermore, autophagy, by recycling cellular components and providing essential nutrients, can promote cancer cell survival during detachment ^[7][12]. Targeting these mechanisms holds promise for the development of therapies aimed at restoring anoikis sensitivity in cancer cells and curbing their metastatic potential.

6. Therapeutic Approaches Targeting Anoikis Resistance

The idea of targeting anoikis resistance as a therapeutic strategy in cancer has gained substantial momentum, with various innovative approaches under exploration ^[10]. One avenue involves the development of apoptosis inducers, which are drugs specifically designed to target the apoptotic machinery in anoikis-resistant cancer cells, potentially reinstating their sensitivity to detachment-induced apoptosis ^[13]. Another promising approach entails the utilization of inhibitors targeting survival signaling pathways such as PI3K/Akt or ERK/MAPK, aiming to disrupt the pro-survival mechanisms that enable cancer cells to withstand the challenges of detachment ^[13]. Additionally, anti-EMT therapies have emerged as a strategy to sensitize cancer cells to anoikis by blocking or reversing the epithelial-mesenchymal transition. Lastly, the combination of autophagy inhibitors with other therapeutic modalities is being explored to enhance the response of cancer cells to anoikis, potentially offering a multifaceted approach to combat metastasis and improve treatment outcomes in cancer patients ^[13].

7. Conclusion

In summary, anoikis stands as a fundamental process in cellular biology, orchestrating cell survival upon detachment from the extracellular matrix (ECM). Dysregulation of anoikis signifies a hallmark of cancer progression, facilitating metastasis, therapy resistance, and unchecked tumor growth. The comprehension of the intricate molecular mechanisms underpinning anoikis and the strategies employed by cancer cells to evade it is imperative for pioneering innovative therapeutic approaches. The pursuit of interventions specifically targeting anoikis resistance emerges as a beacon of hope in the realm of cancer treatment, with the potential to enhance treatment outcomes and curtail metastatic spread. Through these endeavors, we aspire to provide a renewed sense of optimism for patients confronting this formidable disease.