Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming

Abstract

The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure–function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis. Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through “anoikis.” However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis. Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis. Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis. Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis. This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis. In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis.

Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis

“…Anoikis resistance is a common hallmark of metastatic cancer cells that can be exploited to prevent metastasis [6]. However, the molecular mechanisms remain to be profoundly understood.…”

“…Compromised anoikis machinery is required for effectual metastasis of tumor cells to other sites. In other words, anoikis resistance is a precondition and a hallmark for the metastatic potential of tumor cells [3,6]. Targeting anoikis is a promising option for metastasis prevention but calls for a profound understanding of the mechanisms underlying anoikis resistance [6].…”

“…Therefore, how changes in ROS level in tumor cells contribute to anoikis remains to be fully understood. On the other hand, the molecular dynamics after tumor cells detach from the Ivyspring International Publisher ECM contributing to anoikis abrogation and metastasis is yet to be fully demystified [6]. To this effect, we cultured cervical cancer cells in culture dishes to demonstrate low adherence by pre-coating with poly 2-hydroxyethyl methacrylate (polyhema) to mimic ECM detachment.…”

Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis

“…The following studies proved its critical role in the homeostasis of skin [ 8 ], digestive tract [ 9 ], and mammary gland [ 10 ], as well as in physiological processes, such as fibrinolysis [ 11 ], aortic valves [ 12 , 13 ], and vascular remodeling [ 14 ]. Intrinsic cell death molecules such as Bcl-2 family molecules and cytochrome c , extrinsic cell death molecules such as TNFR, DR5, or Fas, and other signaling molecules such as integrins and EGF reportedly modulate anoikis, see reviews for further information [ 15 , 16 ].…”

“…It is well established that integrins protect cells against anoikis [ 15 , 16 ], and worthy to note that the protecting role of different integrins differs in different cell types. For example, integrin α V β 3 is required for angiogenic vascular cell survival during detachment [ 51 ].…”