Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance

Abstract

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.

Keywords: Cancer cell plasticity; Cancer stem cells; Drug resistance; Epithelial-mesenchymal transition; Targeted therapies; Tumor heterogeneity.

Fig. 1

A Illustration of the dynamic interconversion between cancer stem cells (CSCs) and non-CSCs. This figure illustrates the minor yet critical subpopulation of tumor mass known as CSCs. It visually elucidates the phenomenon of phenotypic plasticity that empowers both CSCs and non-CSCs to interchange states depending on various intrinsic and extrinsic cellular properties. Intrinsic factors include epigenetic changes that internally modulate cellular activities, while extrinsic factors encompass elements of the tumor microenvironment that externally influence the cells. The figure offers insight into the dynamic nature of cellular identity within tumor masses, emphasizing the impact of diverse cellular and microenvironmental factors on the CSC and non-CSC states. B Detailed overview of the regulatory network involving key transcription factors and molecules. This figure comprehensively depicts the transcription factors, including Snail1/Snail2, ZEB1/ZEB2, Twist, and LEF-1, whose expression is intricately modulated by multiple signaling pathways. It outlines the various regulatory molecules that can inhibit the functionality of these transcription factors, thus impacting cellular activities. The figure elaborates on the prevention of LEF-1 activation by GSK-3, which hinders its collaboration with β-catenin and also demonstrates GSK-3’s role in barring the stability and nuclear translocation of Snail1/Snail2. Additionally, the figure highlights the suppression of ZEB1/ZEB2 expression by the miR-200 family of miRNAs and the inhibition of GSK-3 and miR-200 by the kinase Akt, which is activated by most EMT signaling pathways

Fig. 2

Detailed representation of TGF receptor–mediated signaling pathways and their regulatory mechanisms. This figure provides a thorough visual exploration of the complex interactions and activities instigated by the binding of TGF ligands to their type II and type III receptors (TGF-RII and TGF-RIII). It illustrates the consequential recruitment and phosphorylation of the type I receptor (TGF-RI), a pivotal action that triggers multiple signaling pathways. This intricate signaling network, including pathways controlled by SMAD2/SMAD3, Ras, and PI3K, is detailed in the figure, emphasizing their crucial role in activating specific transcription factors. The figure elaborates on the cascade effect that ensues, leading to the expression of genes that encode transcription factors instrumental in initiating epithelial to epithelial-to-mesenchymal transition (EMT). Furthermore, the figure delineates the activation of Akt by SMAD-independent pathways, such as PI3K and ILK. Akt’s subsequent limitation of GSK-3β activity is visually explained. This limitation is significant as GSK-3β is a kinase that inhibits the nuclear translocation of Snail and β-catenin, critical components in cellular transformation and movement. Moreover, Fig. 3 highlights the role of Smurf2 and SMAD6/SMAD7 in inhibiting SMAD signaling. It explains Smurf2’s function in degrading the active complex SMAD2/SMAD3/SMAD4 and SMAD6/SMAD7’s blockage of SMAD2/SMAD3 binding and phosphorylation at TGF-Rs

Fig. 3

Detailed mechanism of EMT-related gene activation via various pathways. This figure describes the mechanisms that underlie the Dvl-dependent regulation of GSK-3β, a key kinase involved in the breakdown of cytoplasmic β-catenin. The illustration outlines the sequence initiated by the binding of Wnt ligands to Frizzled receptors. This binding and activation event facilitates the nuclear localization and accumulation of β-catenin, subsequently activating the LEF-1 transcription factor. The figure further emphasizes the consequential stimulation of the production of several EMT-related genes, which are critical in tumor progression and metastasis. The processes leading to the Notch intracellular domain (ICD) release by the γ-secretase enzyme in response to the interaction between JAG2 and its receptor Notch are also depicted. The figure highlights the roles of various pathways, including ERK and NF-κB, activated by the Notch ICD, in the induction of the Snail1/Snail2 and LEF-1 transcription factors

Fig. 4

A Exploring the origins of cellular plasticity and innovative therapeutic strategies. This figure delves into the intricate origins of cellular plasticity, providing a comprehensive visualization of the multifactorial mechanisms that contribute to this phenomenon. It maps out the path from initial cellular changes to the manifestation of plasticity, detailing the genetic, epigenetic, and environmental factors at play. The figure concurrently showcases emerging therapeutic strategies that precisely target cellular plasticity, highlighting their modes of action, potential benefits, and associated challenges. B Comprehensive overview of therapeutic approaches targeting tumor cell adaptability. This figure provides a comprehensive, visually engaging overview of the innovative therapeutic approaches that strategically target the adaptability of tumor cells. The figure details three primary, combinable approaches for effectively addressing tumor cell plasticity. The first approach elaborated upon is the prevention of tumor cell plasticity, outlining potential methods and strategies for this preventive action. The second approach discussed is the reversal of phenotypic switching, which offers insight into the mechanisms that can revert the altered phenotypes to their original states. The third focus is centering therapy on the induced therapy-resistant tumor cells, with the figure delineating the prospective therapies and their targeted actions