Plasticity of Cancer Cells in Tumor Initiation Progression and Metastasis
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Plasticity of Cancer Cells in Tumor Initiation Progression and Metastasis
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Plasticity of Cancer Cells in Tumor Initiation Progression and Metastasis.
Cell plasticity refers to the ability of cells to respond to intrinsic or extrinsic factors, reprogram themselves, and change their fate and identity. Plasticity is not limited to stem cells;
cells can dedifferentiate (revert differentiated cells to undifferentiated state), transdifferentiate (convert differentiated cells into another lineage), and undergo epithelial-mesenchymal transition (EMT) to acquire different phenotypes.
Plasticity is crucial for restoring homeostasis after tissue injury, inflammation, or aging.
However, it can also drive tumor initiation. During cancer progression, tumor cells switch between different cellular states, primarily mediated by cellular plasticity, to overcome selective pressures.
Thus, cellular plasticity largely contributes to heterogeneity and adaptability within tumors, significantly impacting tumor growth, metastasis, and drug resistance.
Therefore, understanding the intrinsic and extrinsic mechanisms driving cellular plasticity, and how these mechanisms promote tumor growth, proliferation, metastasis, and drug resistance, is crucial for advancing cancer therapies.
Plasticity in Tumor Initiation
The ability of differentiated cells to revert to a stem-like state is significant in tumor initiation.
Certain oncogenic drivers influence plasticity during tumorigenesis.
Tumor suppressor genes like TP53, RB1, and PTEN regulate developmental differentiation programs; their dysfunction leads to cancer initiation.
For instance, in adenocarcinoma, single-potent basal stem cells and luminal stem cells can regain multipotency during tumorigenesis. In murine prostate tumor development, Pten loss in basal cells promotes their transition to luminal cells and further differentiation into tumor cells.
In murine breast cancer, expression of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (Pik3ca) H1047R induces multipotency in progenitor cells during early tumorigenesis, laying the foundation for intratumoral heterogeneity.
Inflammation also regulates plasticity during regeneration and tumor initiation.
After inflammation, Lgr5+ stem cells are lost in the mouse intestine, inducing re-entry of Paneth cells into the cell cycle, acquiring stem-like properties, and aiding tissue regeneration.
In the absence of inflammation, only intestinal stem cells induce tumor formation upon Apc loss.
Co-deletion of Apc and Nfkbia activates the NF-κB signaling, inducing non-stem cells to form tumors, demonstrating inflammation’s role in expanding tumor-initiating potential.
Plasticity in Tumor Growth and Proliferation
Cancer stem cells (CSCs) express stem-like programs, self-renew, sustain tumor growth, and give rise to less proliferative tumor cells. While CSCs primarily generate less proliferative subpopulations without fully reverting to a CSC state, evidence suggests both CSCs and non-CSCs are plastic and can undergo phenotypic transitions under certain conditions.
For example, gene knockout of Lgr5+CSCs within xenografted murine cancerous organs limits tumor growth without regression. Tumors are maintained by proliferative Lgr5- cells, which replenish the CSC pool.
Upon cessation of knockout, Lgr5+CSCs reappear, rapidly regenerating the tumor, indicating plasticity in highly differentiated tumor cells after CSC ablation. This finding is supported by patient-derived organoids, highlighting the insufficiency of targeting CSCs without addressing plasticity.
CSC niches comprise heterogeneous and interacting cell populations, playing a crucial role in CSC regulation and promoting cancer cell plasticity.
The vascular niche, highly vascularized areas comprising endothelial cells, pericytes, smooth muscle cells, and immune cells, creates an environment favoring tumor progression, invasion, and metastasis by influencing stemness, chemotherapy resistance, and invasion.
Endothelial cells maintain CSC stemness via Wnt and Notch ligands secretion and direct cell-cell interactions.
They also enhance invasion and proliferation through IL-8 and IL-6 secretion. Conversely, CSCs induce vascular sprouting by secreting vascular endothelial growth factor (VEGF), thereby regulating CSC renewal.
Besides attracting and reprogramming endothelial cells during tumor initiation, CSCs can also undergo endothelial-like transition.
Hypoxia promotes CSC stemness and acquisition of endothelial features. Differentiation of tumor cells into endothelial cells has been confirmed in human and murine cancer models, though its biological relevance remains unclear.
Cancer-associated fibroblasts (CAFs) contribute to CSC maintenance through cytokine secretion, including HGF, IGF2, TGFβ1, IL-6, and various chemokine ligands. They also participate in matrix remodeling through matrix metalloproteinase secretion and deposition of collagen and hyaluronic acid.
Immune cells are crucial components of the CSC niche. Communication between CSCs and macrophages, particularly through direct interactions, promotes EMT, inducing EphA4 expression in CSCs, enhancing cytokine secretion, and maintaining stemness.
Cytokines secreted by macrophages, such as TGF-β, IL-6, and Wnt ligands, primarily activate STAT-3 signaling, promoting tumor cell stemness.
Plasticity in Metastatic Cascade
Metastasis involves a multi-step cascade, including cancer cells detaching from primary tumors, locally invading surrounding tissue, infiltrating blood or lymphatic vessels, extravasating, colonizing secondary organs, and establishing secondary tumor growth.
Evidence suggests that only specific subpopulations of tumor cells, termed metastasis-initiating cells (MIC), can drive metastasis. MICs exhibit high plasticity, displaying varying degrees of stemness, EMT, and metabolic plasticity throughout the metastatic cascade.
Metastasis Initiation
EMT plays a critical role in tumor metastasis. EMT can be triggered by various transcription factors, with SNAI1, SNAI2, Twist1, ZEB1, and ZEB2 considered core regulators, inducing classic EMT and often co-expressed. EMT promotes stemness, generating secondary tumors from MICs.
In the course of tumorigenesis, cancer cell metabolic phenotypes can change based on nutrient availability, proliferation rates, and mutational burden.
The metastatic cascade enhances adaptability of metastatic tumor cells to overcome nutritional fluctuations and oxidative stress, with MICs typically exhibiting increased anaerobic glycolysis.
Dysregulated oxidative phosphorylation occurs in various cancers, correlating with EMT and poor prognosis.
The niche is crucial for inducing EMT and metastasis initiation. Fibroblasts support tumor cells by promoting migration, invasion, angiogenesis, and vascular generation, favoring tumor cell plasticity.
Tumor cell-secreted TGF-β is essential for recruiting and activating fibroblasts in the initial step of tumorigenesis.
Activated fibroblasts subsequently induce self-secretion and paracrine secretion of TGF-β, inducing EMT in tumor cells and promoting immune evasion. Additionally, macrophages influence EMT and tumor cell plasticity.
Local Invasion and Dissemination of Tumor Cells
Tumor cells in a fully epithelial-to-mesenchymal transition (EMT) state invade surrounding tissues, while those in a hybrid EMT state facilitate collective migration. Leading-edge tumor cells exhibit a more pronounced EMT phenotype compared to follower cells.
Hybrid EMT cells’ collective migration is associated with increased plasticity, stemness, invasiveness, and metastatic capacity.
Subsequently, tumor cells infiltrate blood vessels as circulating tumor cells (CTCs), some surviving and extravasating into secondary organs. In the secondary organ, they proliferate for metastatic growth or enter dormancy.
Both single and clustered CTCs display changes in epithelial and mesenchymal marker expression, exhibiting plasticity during tumor progression.
Plasticity of different CTC phenotypes has been linked to cancer advancement and chemotherapy resistance.
Within circulation, CTCs experience heightened oxidative stress, leading tumor cells to upregulate antioxidant production to prevent reactive oxygen species (ROS)-mediated cell death.
Melanoma CTCs migrating through blood vessels undergo higher oxidative stress and ferroptosis compared to those through lymphatics, relying on the ferroptosis inhibitor GPX4 for survival, while lymphatic migration-dependent CTCs rely on antioxidants like oleic acid and glutathione.
Tumor cells survive in the bloodstream by being encapsulated by platelets and interacting with leukocytes, fibroblasts, macrophages, and endothelial cells.
The crosstalk between tumor cells and macrophages is crucial for CTC-mediated colon cancer metastasis, promoting EMT-related plasticity.
Neutrophil-tumor cell clusters seem more metastatic than individual tumor cell clusters due to increased cell cycle progression mediated by neutrophils within tumor cells.
Interaction with platelets provides resistance against shear forces, activating inducible EMT through TGF-β and NF-κB pathways.
Metastatic Niche
The metastatic niche, formed by disseminating signals from stromal cells, extracellular matrix, and stimuli, creates a specific microenvironment.
Evidence suggests that tumor cells prime their niches before colonization.
Pre-metastatic niche regulation involves vascular leakage, reprogramming of resident cells, and recruitment of bone marrow-derived cells.
Mechanisms are induced by disseminating cells at the metastatic site, but primary tumors also remotely reprogram through soluble factors and exosomes.
Reprogramming around blood vessels entails increased ECM component deposition and expression, establishing a permissive soil for metastasis.
Metastatic Colonization
Epithelial-to-mesenchymal transition (EMT) reversal through mesenchymal-to-epithelial transition (MET) can promote metastatic colonization
Loss of E-cadherin increases invasiveness, but its expression protects cells from oxidative stress during dissemination, promoting colonization.
Tumor cells can form heterotypic connections using E-cadherin and N-cadherin expressed by stromal cells in the metastatic niche, facilitating survival and growth.
Several studies highlight the necessity of downregulating EMT factors for metastatic seeding.
Twist1-mediated EMT promotes invasion and CTC circulation in squamous cell carcinoma, while Twist1 downregulation aids metastatic colonization.
PRRX1 promotes invasion in pancreatic ductal adenocarcinoma; its actions are mediated by two subtypes: PRRX1b promotes EMT, invasion, and migration, while PRRX1a stimulates liver metastatic growth, tumor differentiation, and MET. Thus, metastatic propagation requires a switch from early PRRX1b to late PRRX1a in the metastatic cascade.
Tumor Dormancy
Disseminated tumor cells can enter a dormant state at metastatic sites. This growth arrest results from poor vascularization, immune destruction, lack of nutrients, growth factors, or inhibitory signals from the microenvironment (e.g., TGF-β), maintaining a balance between proliferation and apoptosis.
Dormant cells feature activated survival pathways, cell cycle arrest, sustained unfolded protein responses, and hypoxia.
Dormancy enables evasion of immune responses and chemotherapy, remaining undetectable by imaging techniques and potentially causing relapse even years after clinical remission.
Mechanisms of entering and exiting dormancy remain incompletely understood.
Transition between dormancy states displays plasticity, but whether EMT or MET can promote reactivation and awakening from dormancy remains unclear.
Dormancy is tightly controlled by the microenvironment. III collagen secretion by tumor cells at the metastatic site favors dormancy, while disruption of matrices rich in III collagen induces awakening and proliferation of dormant cells via the discoidin domain receptor tyrosine kinase 1 (DDR1)-mediated STAT1 signaling.
Age-related changes in the microenvironment during aging also play a role in entering or exiting dormancy; fibroblast age-associated changes are associated with increased melanoma metastasis.
Aging fibroblasts exhibit elevated secretion of Wnt antagonist sFRP2, inducing resistance to ROS-mediated DNA damage response in melanoma cells, imparting treatment resistance and increasing metastasis.
Aged lung fibroblasts secrete more sFRP1 and block Wnt5a-induced dormancy induction, promoting metastatic growth.
Age-related changes in the microenvironment likely explain the recurrence of metastatic lesions years after treatment.
Summary
Tumor cell plasticity plays a crucial role in cancer initiation, progression, metastasis, and treatment resistance.
Different plasticity patterns sustain tumor growth in various proliferation states and involve cancer stem cells (CSCs), an essential aspect of the metastatic cascade.
Plasticity also allows tumor cells to evade selective pressures and develop resistance.
Therefore, a deeper understanding of the intrinsic and extrinsic mechanisms regulating tumor cell plasticity paves the way for novel therapeutic strategies, ultimately improving patient survival.
Reference:
1.Cancer cell plasticity during tumor progression, metastasis and response to therapy. Nat Cancer.2023 Aug 3
Plasticity of Cancer Cells in Tumor Initiation Progression and Metastasis.
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