NOTCH2 signaling, crucial for maintaining hepatocyte identity and function, may falter in HCC, disrupting the normal genetic programming of hepatocytes. This disruption could lead to the downregulation or loss of hepatocyte-specific genes, fostering a cellular milieu conducive to transdifferentiation into other cell types, thus fostering tumor heterogeneity [161]. Furthermore, dysregulated NOTCH2 expression in HCC may spur the activation of alternative differentiation pathways or lineage-specifying transcription factors. By invoking programs associated with intestinal epithelial cells or pancreatic progenitor cells, NOTCH2 dysregulation might drive transdifferentiation of HCC cells into phenotypes resembling these lineages. Moreover, NOTCH2 signaling's role in regulating cellular plasticity and fate determination is pertinent. Dysregulated NOTCH2 expression might disrupt the delicate balance between self-renewal and differentiation, heightening cellular plasticity within the HCC microenvironment and facilitating the adoption of alternative cell fates, thereby contributing to intratumoral heterogeneity [162]. Additionally, dysregulated NOTCH2 expression in HCC may perturb signaling pathways involved in cell fate determination and differentiation. Crosstalk between NOTCH2 signaling and pathways like Wnt/β-catenin and TGF-β could lead to aberrant pathway activation, further promoting transdifferentiation and augmenting tumor heterogeneity. Finally, the interplay of NOTCH2 with other transcription factors and co-regulators is important. Dysregulated NOTCH2 expression might disrupt these interactions, culminating in aberrant activation or repression of downstream target genes, thus contributing to the emergence of transdifferentiation and heterogeneity features within HCC tumors [163, 164].
Presence or Role in Other Tumors:
In pancreatic cancer, HNF6's involvement has been underscored, influencing the regulation of genes pertinent to pancreatic cell differentiation and function. Dysregulated expression of HNF6 within this context may foster tumor initiation, progression, and metastasis, a correlation that aligns with poorer prognosis and aggressive tumor behavior among affected patients [170]. Similarly, in colorectal cancer (CRC), HNF6's impact extends to the orchestration of intestinal epithelial cell dynamics. Perturbations in HNF6 expression levels have been noted, potentially influencing tumor development and progression. The expression levels of HNF6 correlate with critical parameters like tumor grade, metastatic potential, and patient survival, hinting at its promise as both a prognostic marker and a therapeutic target in CRC [171]. Furthermore, in prostate cancer, HNF6 emerges as a significant player in disease trajectory, modulating genes crucial for prostate epithelial cell differentiation and function. Dysregulated HNF6 expression has been implicated in heightened cancer aggressiveness and metastatic potential, aligning with observations of its association with tumor stage, recurrence rates, and patient outcomes. In breast cancer, HNF6's presence in tumor tissues suggests its potential involvement in disease progression. Dysregulated expression of HNF6 correlates with indicators of aggressive tumor behavior, metastatic propensity, and patient prognosis. Its association with tumor grade, hormone receptor status, and patient survival underscores its relevance as a prognostic marker and therapeutic target in breast cancer management [172]. In neuroendocrine tumors, HNF6's regulatory influence over neuroendocrine cell differentiation and function signifies its role in tumor development and progression within this context. Dysregulated HNF6 expression levels are implicated in tumor aggressiveness and hormone secretion, aligning with observations of its correlation with tumor grade, hormone secretion levels, and patient outcomes. This highlights its potential utility as a prognostic marker and therapeutic target in neuroendocrine tumors [173, 174].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
The dysregulated expression of HNF6 in HCC can disturb the genetic blueprint essential for hepatocyte integrity, possibly leading to the attenuation or loss of hepatocyte-specific genes. Consequently, this deviation from the hepatocyte differentiation state could foster an environment conducive to transdifferentiation, thus fostering tumor heterogeneity [175]. Furthermore, the aberrant expression of HNF6 may not only perturb the conventional differentiation pathways but also activate alternative programs or lineage-specifying factors within HCC cells. Drawing parallels with its role in pancreatic differentiation, dysregulation of HNF6 might propel HCC cells towards acquiring pancreatic-like phenotypes, thereby further enhancing tumor heterogeneity. Moreover, HNF6's involvement extends to the regulation of cellular plasticity and fate determination. In the context of HCC, dysregulated HNF6 expression could disrupt the delicate equilibrium between self-renewal and differentiation, thereby augmenting cellular plasticity. This augmented plasticity may empower HCC cells to adopt diverse cellular identities, thereby contributing to intratumoral heterogeneity [176]. Additionally, dysregulated HNF6 expression in HCC could disrupt signaling pathways important for cell fate determination and differentiation. HNF6 crosstalks with pathways like Wnt/β-catenin and TGF-β, its dysregulation might trigger aberrant pathway activation, fostering transdifferentiation events and fueling tumor heterogeneity. Finally, HNF6's interactions with various transcription factors and co-regulators play a crucial role in governing gene expression networks crucial for cell fate decisions. In the context of HCC, dysregulated HNF6 expression could perturb these interactions, resulting in aberrant downstream gene regulation. This dysregulation may culminate in the emergence of transdifferentiation events and contribute significantly to the heterogeneity observed within HCC tumors [177, 178].
10. ONECUT2/ HNF6β
Expression in Other Cell-Types:
ONECUT2, also known as HNF6β, extends its influence beyond hepatocytes, manifesting crucial roles in various cell types during development. In pancreatic progenitor cells, ONECUT2 orchestrates pancreatic development by steering the differentiation of both endocrine and exocrine cell lineages. It fosters the emergence of vital endocrine cell types like insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells [179]. Additionally, ONECUT2 contributes to the formation of pancreatic exocrine cells such as acinar and ductal cells, essential for digestive enzyme secretion and pancreatic fluid homeostasis. Within the central nervous system, ONECUT2 exerts its influence during neuronal development. By guiding neuronal differentiation and axonal growth, it facilitates the establishment of neuronal circuits and synaptic connections. These actions contribute to the development of diverse neuronal subtypes crucial for sensory and motor functions, including motor neurons, interneurons, and sensory neurons [180]. In intestinal epithelial cells, ONECUT2 regulates intestinal development and maintenance. It steers the differentiation of intestinal stem cells into specialized epithelial cell types like absorptive enterocytes and secretory goblet cells. Moreover, ONECUT2 bolsters intestinal barrier function and mucosal immunity, safeguarding against microbial intrusion and preserving intestinal equilibrium. Within the adrenal cortex, ONECUT2 participates in adrenal gland development by overseeing the differentiation of steroidogenic cells. These cells, nestled in distinct zones like the zona glomerulosa and zona fasciculata, synthesize essential steroid hormones like cortisol and aldosterone, thereby contributing to systemic homeostasis. Finally, in renal tubular epithelial cells, ONECUT2 plays a crucial role in kidney development [181]. By regulating the differentiation of nephron progenitor cells into various renal tubular epithelial cell types, it ensures the formation of proximal tubule cells, distal tubule cells, and collecting duct cells. Furthermore, ONECUT2 upholds renal tubular integrity and function, essential for maintaining electrolyte balance and fluid homeostasis [182].
Presence or Role in Other Tumors:
ONECUT2, also termed HNF6β, emerges as a significant player in the context of tumorigenesis and tumor progression across a spectrum of cancer types. In pancreatic cancer, ONECUT2 exhibits elevated expression levels, thereby fostering tumor growth, invasion, and metastasis by orchestrating the activation of genes governing proliferation, survival, and epithelial-mesenchymal transition (EMT). The heightened ONECUT2 expression correlates with dismal prognostic outcomes and reduced survival rates among pancreatic cancer patients [183]. Similarly, in colorectal cancer, ONECUT2 is overexpressed, exerting its influence on tumor cell behavior by fueling proliferation, migration, and invasion through the regulation of key genes involved in cell cycle control, apoptosis resistance, and EMT. Elevated ONECUT2 levels align with advanced tumor stage, lymph node metastasis, and inferior prognosis in colorectal cancer patients [184]. Prostate cancer presents another arena where ONECUT2 expression escalates, fostering tumor cell proliferation, survival, and androgen receptor (AR) signaling, thereby steering disease progression. Its regulatory influence extends to genes important for hormone response, cell cycle regulation, and metastasis, correlating with aggressive tumor phenotypes, biochemical recurrence, and castration-resistant prostate cancer (CRPC). In breast cancer, ONECUT2 emerges as an upregulated entity, perpetuating tumor cell proliferation, invasion, and metastasis by orchestrating gene networks governing cell cycle progression, angiogenesis, and tumor microenvironment remodeling [185]. Its heightened expression is associated with adverse prognostic indicators, metastatic dissemination, and resistance to therapy among breast cancer cohorts. In neuroendocrine tumors, ONECUT2 assumes an augmented expression profile, where it modulates genes instrumental in neuroendocrine cell differentiation and function. This phenomenon culminates in heightened tumor cell proliferation, hormone secretion, and metastatic propensity, aligning with advanced tumor stage, hormone hypersecretion, and compromised patient outcomes [186].
ONECUT2 emerges as a significant contributor to tumorigenesis and tumor progression across diverse cancer types, exerting its influence through gene regulatory networks that dictate crucial aspects of cancer cell behavior and disease trajectory [187].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
ONECUT2/HNF6β, a critical regulator of hepatocyte development and function, holds sway over the genetic programming essential for maintaining the identity of hepatocytes. In the context of HCC, aberrant expression of ONECUT2/HNF6β may perturb this delicate balance, resulting in the downregulation or loss of hepatocyte-specific genes, thereby paving the way for a cellular milieu conducive to transdifferentiation into alternative cell types, thereby fostering heterogeneity within the tumor [188]. Moreover, dysregulated expression of ONECUT2/HNF6β in HCC cells could instigate the activation of alternative differentiation pathways or lineage-specifying transcription factors, drawing parallels from its involvement in pancreatic cell differentiation and function. This aberration may propel the transdifferentiation of HCC cells towards acquiring a pancreatic-like phenotype, thereby augmenting the spectrum of cellular diversity within the tumor microenvironment. Furthermore, ONECUT2/HNF6β's involvement in regulating cellular plasticity and fate determination unveils another layer of complexity. Dysregulation of its expression in HCC may disrupt the equilibrium between self-renewal and differentiation, fostering an environment conducive to enhanced cellular plasticity [189]. This phenomenon could empower HCC cells with the ability to adopt alternative cell fates, thereby fueling the inherent heterogeneity observed within the tumor. Additionally, dysregulated expression of ONECUT2/HNF6β in HCC holds the potential to impinge upon signaling pathways crucial for cell fate determination and differentiation [190]. Through crosstalk with pathways such as Wnt/β-catenin and TGF-β, dysregulation of ONECUT2/HNF6β may trigger aberrant activation of these pathways, thereby orchestrating transdifferentiation processes and contributing to the heterogeneous landscape within the tumor microenvironment. Moreover, the interplay of ONECUT2/HNF6β with other transcription factors and co-regulators underscores its role in orchestrating gene expression networks important for cell differentiation and function. Dysregulated expression of ONECUT2/HNF6β in HCC may perturb these interactions, culminating in aberrant activation or repression of downstream target genes, thus potentiating the emergence of transdifferentiation and heterogeneity features within the tumor microenvironment [191, 192].
11. TBX3/18
Expression in Other Cell-Types:
TBX3 and TBX18, members of the T-box transcription factor family, exert important roles in embryonic development, extending beyond hepatocytes to various other cell types. In cardiac cells, TBX3 and TBX18 are instrumental in shaping the architecture of the heart [193]. TBX3 contributes to the specification of pacemaker cells within the sinoatrial node, thus regulating heart rhythm, while TBX18 plays a crucial role in the differentiation and sustenance of cardiomyocytes, essential for cardiac function and the formation of the cardiac conduction system. These transcription factors also exert influence over the musculoskeletal system, participating in the development and differentiation of skeletal muscle, bone, and cartilage. TBX3 influences muscle development and regeneration, as well as skeletal patterning during limb formation, whereas TBX18 is vital for skeletal muscle and bone development, along with the specification of cartilage progenitor cells during embryogenesis [194]. Furthermore, TBX3 and TBX18 contribute significantly to the formation of urogenital structures, including the kidneys, bladder, and reproductive organs. TBX3 aids in the formation of the ureteric bud and branching morphogenesis of the kidney, as well as the development of the bladder and urethra, whereas TBX18 is involved in the differentiation of smooth muscle cells in the urinary tract and reproductive organs. In neural crest-derived cells, TBX3 and TBX18 play crucial roles in the development of craniofacial structures, peripheral neurons, and melanocytes [195]. TBX3 is integral to the patterning of craniofacial tissues and the specification of neural crest-derived cell lineages, while TBX18 contributes to the development of sensory neurons, glial cells in the peripheral nervous system, and the migration and differentiation of melanocytes. Moreover, TBX3 and TBX18 are implicated in the development of lymphatic vessels and lymphatic endothelial cells, crucial for immune function and tissue fluid homeostasis. TBX3 governs the specification and maintenance of lymphatic endothelial cell identity, as well as lymphangiogenesis, while TBX18 participates in the differentiation of lymphatic endothelial cells from venous endothelial precursors, thereby contributing to the formation of the lymphatic vasculature [196].
Presence or Role in Other Tumors:
TBX3 and TBX18, both important in embryonic development as transcription factors, extend their influence to tumorigenesis and tumor progression across various cancer types. In breast cancer, TBX3's overexpression is linked to tumor advancement and metastasis, as it governs genes involved in cell proliferation, epithelial-to-mesenchymal transition (EMT), and metastasis, thereby influencing patient prognosis [197]. Similarly, TBX3 plays a significant role in melanoma progression and metastasis, regulating genes crucial for cell proliferation, invasion, and migration. Its heightened expression in melanoma tumors, particularly in metastatic lesions, correlates with advanced tumor stage and poor patient prognosis. In bladder cancer, elevated TBX3 expression levels are associated with tumor aggressiveness and adverse clinical outcomes, as it modulates genes governing cell proliferation, invasion, and metastasis, highlighting its significance in disease progression [198]. Dysregulation of TBX3 expression in lung cancer, especially non-small cell lung cancer (NSCLC), underscores its role in tumor proliferation, invasion, and metastasis, with its expression levels being indicative of tumor grade, lymph node involvement, and patient survival. Conversely, TBX18's involvement in prostate cancer is important, where its altered expression correlates with tumor aggressiveness, recurrence, and poor patient outcomes, as it regulates genes pertinent to cell proliferation, invasion, and metastasis. Moreover, in colorectal cancer (CRC), dysregulated expression levels of both TBX3 and TBX18 contribute to tumor progression and metastasis, influencing genes related to cell proliferation, invasion, and metastasis, thereby affecting patient survival and disease outcome [199].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
TBX3 and TBX18 are crucial in maintaining hepatocyte identity during development, essential for the normal genetic programing of hepatocytes. Dysregulated expression of TBX3/18 in hepatocellular carcinoma (HCC) may disrupt this programing, potentially leading to the downregulation or loss of hepatocyte-specific genes. Consequently, this loss of differentiation state could foster a cellular environment conducive to transdifferentiation into other cell types, thereby augmenting heterogeneity within the tumor [200]. Furthermore, dysregulated TBX3/18 expression in HCC cells might activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, TBX3's involvement in cardiac and musculoskeletal cell development, along with TBX18's role in cardiac and urogenital cell development, suggests their potential to induce alternative differentiation programs in HCC cells. This could lead to the transdifferentiation of HCC cells into cell types characteristic of other tissues. Moreover, TBX3 and TBX18 are implicated in regulating cellular plasticity and fate determination across various cell types. Their dysregulated expression in HCC could disrupt the balance between self-renewal and differentiation, resulting in enhanced cellular plasticity [201]. Consequently, HCC cells may acquire the ability to adopt alternative cell fates, contributing further to tumor heterogeneity. Additionally, dysregulated TBX3/18 expression in HCC may influence signaling pathways crucial for cell fate determination and differentiation. Their interaction with signaling pathways such as Wnt/β-catenin, which is implicated in HCC pathogenesis, suggests a potential role in promoting transdifferentiation and heterogeneity within the tumor microenvironment. Furthermore, the interplay between TBX3/18 and other transcription factors and co-regulators is critical for regulating gene expression networks involved in cell differentiation and function [202, 203].
12. Wnt/β-catenin pathway
Expression in Other Cell-Types:
The Wnt/β-catenin signaling pathway stands as a regulator of development and homeostasis across various cell types, extending beyond hepatocytes. In embryonic stem cells (ESCs), this pathway assumes a crucial role in maintaining pluripotency and self-renewal [204]. Activation of Wnt signaling fosters ESC proliferation while preventing differentiation, thus preserving the undifferentiated state. Within the developing nervous system, the Wnt/β-catenin pathway governs the proliferation, differentiation, and migration of neural progenitor cells (NPCs). Activation of Wnt signaling expands neural progenitor cell populations and orchestrates the specification of neuronal and glial lineages [205]. For osteoblasts and chondrocytes, the Wnt/β-catenin pathway plays critical roles in skeletal development and bone homeostasis. It governs the proliferation and differentiation of osteoblast progenitors, promoting bone formation, and regulates chondrocyte differentiation, crucial for cartilage development and endochondral ossification. In the intestinal epithelium, the Wnt/β-catenin pathway is indispensable for development and maintenance [206]. It oversees the proliferation and differentiation of intestinal stem cells within the crypts, fostering epithelial cell renewal and tissue regeneration. Dysregulation of Wnt signaling in intestinal epithelial cells is associated with intestinal disorders and colorectal cancer. Regarding hair follicle stem cells, the Wnt/β-catenin pathway regulates their activation, proliferation, and differentiation in the skin. Activation of Wnt signaling supports hair follicle regeneration and hair growth, while its inhibition precipitates hair follicle degeneration and alopecia. In the realm of immune cells, the Wnt/β-catenin pathway plays a multifactorial role in development and function. It oversees immune cell differentiation, activation, and effector functions across T cells, B cells, and dendritic cells, thereby contributing to both innate and adaptive immune responses [207].
Presence or Role in Other Tumors:
The Wnt/β-catenin signaling pathway emerges as a frequent target of dysregulation in various tumors, significantly contributing to tumorigenesis, tumor progression, and metastasis. In colorectal cancer (CRC), dysregulation of the Wnt/β-catenin pathway stands as a hallmark, characterized by mutations in APC, CTNNB1 (encoding β-catenin), or other pathway components. These mutations lead to aberrant activation of Wnt signaling, fostering tumor initiation and progression [208]. Activation of Wnt signaling fuels the proliferation, survival, and invasion of CRC cells, correlating with poor prognosis. Similarly, in hepatocellular carcinoma (HCC), frequent activation of the Wnt/β-catenin pathway contributes significantly to hepatocarcinogenesis. Mutations in CTNNB1 or AXIN1, resulting in β-catenin stabilization and nuclear translocation, are prevalent in HCC. This activation promotes HCC cell proliferation, survival, and metastasis, correlating with tumor aggressiveness and unfavorable patient outcomes. Dysregulated Wnt/β-catenin signaling is also implicated in various subtypes of breast cancer, where its activation promotes cell proliferation, survival, and metastasis [209]. The crosstalk between Wnt signaling and hormone receptor pathways, such as the estrogen receptor and HER2, contributes to endocrine therapy resistance and tumor recurrence. In lung cancer, particularly non-small cell lung cancer (NSCLC), aberrant activation of the Wnt/β-catenin pathway is frequently observed. Mutations in Wnt pathway components or alterations in Wnt ligand expression disrupt Wnt signaling regulation, fostering NSCLC cell proliferation, invasion, and resistance to therapy, correlating with advanced tumor stage and poor patient outcomes. Moreover, dysregulated Wnt/β-catenin signaling plays a significant role in pancreatic cancer progression. Mutations in Wnt pathway components or alterations in Wnt ligand expression drive aberrant activation of Wnt signaling in pancreatic cancer cells, promoting proliferation, invasion, and metastasis, and correlating with tumor aggressiveness and poor patient prognosis [210]. In melanoma, the Wnt/β-catenin pathway is also dysregulated, contributing to disease progression and metastasis. Activation of Wnt signaling promotes melanoma cell proliferation, survival, and invasion, correlating with tumor aggressiveness and unfavorable patient outcomes [211].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
The Wnt/β-catenin pathway stands out as an important regulator in maintaining hepatocyte identity and function. However, in hepatocellular carcinoma (HCC), dysregulated activation of this pathway can lead to the downregulation of hepatocyte-specific genes, resulting in the loss of hepatocyte identity. Consequently, this loss of differentiation state may create an environment conducive to transdifferentiation into other cell types, thereby contributing to the tumor's heterogeneity [212]. Furthermore, dysregulated Wnt/β-catenin signaling in HCC cells can activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, it has been associated with the upregulation of genes involved in epithelial-mesenchymal transition (EMT) and stemness, potentially driving transdifferentiation into mesenchymal-like or progenitor-like cell states, thus adding to the tumor's heterogeneity. Moreover, the Wnt/β-catenin pathway's role in regulating cellular plasticity and fate determination is critical. Dysregulated expression of this pathway in HCC may enhance cellular plasticity, enabling cells to adopt alternative fates. This plasticity fosters the emergence of heterogeneous cell populations within the tumor, including those with stem-like properties, further contributing to its complexity [213]. Additionally, dysregulated Wnt/β-catenin signaling can influence the tumor microenvironment, altering interactions between cancer cells and stromal cells. Such alterations may promote the emergence of heterogeneous cell populations within the tumor and facilitate the transdifferentiation of HCC cells into cell types characteristic of other tissues, thereby amplifying heterogeneity [214]. Furthermore, the interplay between the Wnt/β-catenin pathway and other signaling pathways implicated in cell fate determination and differentiation is significant. Dysregulated crosstalk between Wnt/β-catenin signaling and pathways such as Notch, Hedgehog, or TGF-β pathways in HCC may exacerbate the emergence of transdifferentiation and heterogeneity features, further complicating the tumor landscape [215, 216, 217].
13. FGF
Expression in Other Cell-Types:
Fibroblast Growth Factors (FGFs) play roles in the development and maintenance of various cell types. In neural cells, FGFs are indispensable for the formation and sustenance of the nervous system, influencing processes such as proliferation, differentiation, and survival of neural progenitor cells, as well as guiding axonal growth and synaptic plasticity, thereby contributing significantly to neurogenesis and gliogenesis [218]. Mesenchymal cells also rely on FGFs for their development and differentiation into different lineages like osteoblasts, chondrocytes, and adipocytes. FGFs orchestrate processes such as bone formation, cartilage development, and adipogenesis, crucial during skeletal development and tissue repair. Moreover, FGFs partake in wound healing, angiogenesis, and fibrosis, essential for tissue integrity and repair across various organs [219]. Epithelial tissues, including those in the skin, lungs, and gastrointestinal tract, depend on FGFs for their development, maintenance, and repair. FGFs regulate epithelial cell behavior, governing proliferation, differentiation, migration, and tissue morphogenesis, contributing significantly to organogenesis and tissue homeostasis. Vascular endothelial cells rely on FGFs for angiogenesis and vascular development [220]. These growth factors modulate endothelial cell functions such as proliferation, migration, tube formation, and blood vessel remodeling, critical for both embryonic vasculogenesis and postnatal vascular maintenance and repair. In muscle cells, FGFs play crucial roles in development and regeneration, particularly in skeletal and cardiac muscle. They regulate processes like myoblast proliferation, differentiation, and fusion, which are vital for muscle growth, repair, and function throughout life. Finally, FGFs exert influence on the development and function of various immune cell types [221]. They regulate immune cell proliferation, differentiation, and activation, as well as cytokine production and inflammatory responses. FGFs contribute to immune cell development in primary lymphoid organs and modulate immune cell trafficking and function in peripheral tissues, thereby playing crucial roles in immune system homeostasis and responses [222].
Presence or Role in Other Tumors:
Fibroblast Growth Factors (FGFs) and their signaling pathways have significant implications in tumorigenesis, tumor progression, and metastasis across various types of cancers. In breast cancer, FGF signaling is frequently dysregulated, with overexpression of FGF ligands and receptors like FGF1, FGF2, and FGFR1 associated with tumor growth, angiogenesis, and metastasis [223]. This signaling cascade promotes breast cancer cell proliferation, survival, invasion, and resistance to therapy, ultimately correlating with poor prognosis. Similarly, dysregulated FGF signaling is evident in lung cancer, particularly in non-small cell lung cancer (NSCLC), where alterations in FGF ligands such as FGF2 and FGFRs contribute to tumorigenesis and progression. FGF signaling in NSCLC fosters cell proliferation, angiogenesis, and metastasis, linking to advanced tumor stage and unfavorable patient outcomes. In colorectal cancer (CRC), FGF signaling plays a crucial role in tumor development and progression, with upregulation of FGF ligands like FGF18 and FGFR4 observed in CRC tumors [224]. This signaling axis promotes CRC cell proliferation, survival, angiogenesis, and invasion, fueling tumor growth and metastasis. Prostate cancer pathogenesis involves dysregulated FGF signaling, characterized by the overexpression of FGF ligands such as FGF8 and FGFR1. This dysregulation contributes to tumor growth, angiogenesis, and progression to castration-resistant prostate cancer (CRPC). FGF signaling drives prostate cancer cell proliferation, survival, and invasion, presenting a potential therapeutic target in CRPC. Pancreatic cancer also exhibits dysregulated FGF signaling, with overexpression of FGF ligands such as FGF2 and FGF19, along with FGFRs, observed in pancreatic tumors [225]. This aberrant signaling promotes pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis, aligning with poor patient outcomes. In melanoma, dysregulated FGF signaling contributes to tumor progression and therapy resistance, with alterations in FGF ligands like FGF2 and FGFRs detected in melanoma tumors. This signaling pathway promotes melanoma cell proliferation, survival, angiogenesis, and invasion, correlating with tumor aggressiveness and unfavorable prognosis [226].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
FGF signaling pathways exhibit the capability to induce alternative differentiation programs in HCC cells, potentially leading to the transdifferentiation of these cells into mesenchymal-like or stem-like states. This induction of alternative pathways can contribute significantly to the heterogeneity within the tumor by generating cell populations with distinct phenotypic and functional characteristics [227]. Moreover, dysregulated FGF expression in HCC can enhance cellular plasticity, allowing tumor cells to adopt alternative cell fates in response to microenvironmental cues or signaling inputs. This heightened plasticity often results in the emergence of diverse cell populations within the tumor, including those exhibiting stem-like properties or alternative lineage markers. Furthermore, FGF signaling can influence the tumor microenvironment by modulating interactions between cancer cells and stromal cells. In HCC, dysregulated FGF expression may alter the composition and function of the tumor microenvironment, fostering the emergence of heterogeneity [228]. For instance, FGF signaling can stimulate processes like angiogenesis, fibrosis, and immune cell recruitment, creating supportive niches for distinct subpopulations of HCC cells. Additionally, FGF signaling has been implicated in the activation of epithelial-mesenchymal transition (EMT), a process associated with increased cellular plasticity and invasive behavior in cancer cells. Dysregulated FGF expression in HCC may induce EMT in certain tumor cells, leading to the acquisition of mesenchymal features and further contributing to tumor heterogeneity, progression, metastasis, and resistance to therapy [229]. Moreover, FGF signaling pathways interplay with other signaling pathways involved in cell fate determination and differentiation. Perturbations in FGF expression in HCC can disrupt the balance of these pathways, leading to the emergence of transdifferentiation and heterogeneity features. For example, interactions between FGF and Wnt/β-catenin signaling pathways have been documented in HCC, highlighting their implications for tumor cell plasticity and heterogeneity [230, 231].
14. HGF
Expression in Other Cell-Types:
Hepatocyte Growth Factor (HGF), also known as scatter factor, exhibits various roles in the development and maintenance of multiple cell types beyond hepatocytes. HGF serves as mitogen for epithelial cells, regulating branching morphogenesis and tubulogenesis in tissues like the lung, kidney, and mammary gland during development [232]. It fosters the proliferation, survival, and migration of epithelial cells, thus contributing significantly to tissue morphogenesis and organ development. Moreover, HGF functions as a key regulator of angiogenesis and vascular development, stimulating endothelial cell proliferation, migration, and tube formation. This activity promotes the formation of new blood vessels during both embryonic development and tissue repair processes, ensuring proper vascularization of developing organs and maintaining vascular homeostasis in adult tissues [233]. In addition, HGF acts as a paracrine factor for mesenchymal cells such as fibroblasts and smooth muscle cells, regulating their proliferation, migration, and differentiation. This influence extends to tissue remodeling, wound healing, and organ fibrosis, where HGF signaling plays key roles in orchestrating mesenchymal-epithelial interactions during organ development and regeneration. Furthermore, HGF and its receptor, c-Met, are expressed in the nervous system, where they contribute to neurogenesis, neuronal migration, and synaptogenesis [234]. HGF supports the proliferation and survival of neural progenitor cells and facilitates neurite outgrowth and branching, thus influencing the development and plasticity of neuronal circuits in the brain and spinal cord. Additionally, HGF signaling is implicated in myogenesis and muscle regeneration, promoting the proliferation and differentiation of myoblasts and facilitating muscle fiber formation and repair. It also regulates myoblast migration and fusion during embryonic development and in response to muscle injury, ensuring proper muscle growth and regeneration. HGF influences the function of various immune cell types, including macrophages, T cells, and dendritic cells, by regulating their migration, cytokine production, and tissue infiltration [235]. This modulation of inflammatory responses and tissue repair processes contributes to immune cell recruitment to sites of injury or inflammation, ultimately aiding in tissue remodeling and regeneration. Overall, HGF plays diverse and crucial roles in the development and maintenance of multiple cell types, including epithelial, endothelial, mesenchymal, neural, muscle, and immune cells. Its signaling pathways are indispensable for tissue morphogenesis, organogenesis, and repair processes throughout the body [236].
Presence or Role in Other Tumors:
Hepatocyte Growth Factor (HGF) and its receptor c-Met play significant roles in tumorigenesis, tumor progression, and metastasis across various types of cancers. In gastric cancer, dysregulated HGF/c-Met signaling is linked to disease progression and unfavorable prognosis. Gastric tumors often exhibit overexpression of HGF and c-Met, promoting tumor cell proliferation, invasion, and metastasis. Moreover, this signaling pathway contributes to angiogenesis and confers resistance to chemotherapy in gastric cancer cases. Similarly, in breast cancer, HGF/c-Met signaling is associated with metastasis and resistance to therapy. Elevated levels of HGF and c-Met are correlated with aggressive cancer phenotypes and adverse patient outcomes [237]. This signaling axis facilitates breast cancer cell migration, invasion, and metastasis to distant sites such as the lung and bone, while also fostering resistance to targeted therapies like HER2 inhibitors and endocrine therapy. In non-small cell lung cancer (NSCLC), dysregulated HGF/c-Met signaling is particularly important in cases of acquired resistance to EGFR inhibitors. Overexpression of HGF and c-Met correlates with tumor progression, metastasis, and poor prognosis among NSCLC patients. The pathway promotes NSCLC cell proliferation, survival, invasion, and resistance to targeted therapies, including EGFR inhibitors and immune checkpoint inhibitors [238]. Moreover, HGF/c-Met signaling is implicated in colorectal cancer (CRC) progression and metastasis. Elevated levels of HGF and c-Met are associated with advanced tumor stage, lymph node metastasis, and unfavorable prognosis in CRC patients. This signaling axis drives CRC cell proliferation, invasion, and metastasis to distant organs like the liver, contributing to resistance against chemotherapy and targeted therapies. Similarly, dysregulated HGF/c-Met signaling is observed in pancreatic cancer, promoting tumor progression, invasion, and metastasis. Overexpression of HGF and c-Met is linked to aggressive cancer phenotypes and poor patient outcomes in pancreatic cancer cases. The pathway facilitates pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis to the liver and peritoneum, while also conferring resistance to chemotherapy and targeted therapies [239].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
Hepatocyte Growth Factor (HGF) plays a crucial role in promoting tumor heterogeneity and progression in Hepatocellular Carcinoma (HCC) through various mechanisms. HGF acts as an inducer of Epithelial-Mesenchymal Transition (EMT), prompting epithelial cells to lose their distinctive features and adopt mesenchymal traits. In HCC, dysregulated HGF expression triggers EMT in hepatocytes, resulting in the loss of hepatocyte-specific characteristics and the acquisition of mesenchymal properties [240]. This transition enhances cellular plasticity, fostering the emergence of diverse cell populations within the tumor. Moreover, HGF signaling pathways can activate alternative differentiation programs in HCC cells. By stimulating the expression of lineage-specific transcription factors and signaling molecules, HGF drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells. This transdifferentiation process contributes to tumor heterogeneity and may fuel tumor progression and resistance to therapy. Additionally, HGF enhances cellular plasticity by promoting stemness and dedifferentiation in HCC cells [241]. Dysregulated HGF expression increases the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. This enhanced cellular plasticity facilitates the emergence of therapy-resistant cell populations within the tumor. Furthermore, HGF can modulate the tumor microenvironment by stimulating the recruitment and activation of stromal cells, such as fibroblasts and immune cells [242]. Dysregulated HGF expression alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations. This microenvironmental modulation sustains tumor heterogeneity and promotes tumor progression. HGF signaling pathways crosstalk with other signaling pathways involved in cell fate determination and differentiation [243, 244].
15. TGF-β
Expression in Other Cell-Types:
Transforming Growth Factor-beta (TGF-β) is a multifunctional molecule involved in the development and maintenance of various cell types throughout the body. TGF-β serves as a crucial regulator of epithelial cell behavior, controlling differentiation, proliferation, and homeostasis [245]. It orchestrates epithelial-mesenchymal interactions during development, facilitating the formation of organs like the lung, skin, and mammary gland. By promoting epithelial cell differentiation while inhibiting proliferation, TGF-β contributes significantly to tissue morphogenesis and organ development. In mesenchymal cells, TGF-β signaling is vital for differentiation, migration, and matrix deposition. It guides the differentiation of mesenchymal stem cells into specialized cell types such as osteoblasts, chondrocytes, and adipocytes, essential for skeletal development and tissue repair. Moreover, TGF-β stimulates fibroblast activation and collagen production, key processes in tissue remodeling, wound healing, and fibrotic conditions. TGF-β signaling is indispensable for vascular development and angiogenesis, crucial for the formation of new blood vessels during embryogenesis and tissue repair [246]. It regulates endothelial cell behaviors like proliferation, migration, and tube formation, facilitating vascular growth and maturation. Additionally, TGF-β modulates interactions between endothelial cells and pericytes, as well as the deposition of basement membrane components, promoting vascular stability. In the immune system, TGF-β plays critical roles in cell differentiation, activation, and function. It regulates the differentiation of T cells, B cells, and macrophages, along with cytokine production and immune responses. Acting as an immune suppressor, TGF-β dampens inflammation and fosters immune tolerance in peripheral tissues [247]. Dysregulated TGF-β signaling is associated with conditions like autoimmune diseases and cancer immunosuppression. TGF-β signaling is also involved in neurogenesis, neuronal migration, and synaptogenesis within the developing nervous system. It guides the proliferation and differentiation of neural progenitor cells while influencing neurite outgrowth and branching. Additionally, TGF-β modulates synaptic plasticity and neurotransmitter release, contributing to the formation and function of neural circuits [248].
Presence or Role in Other Tumors:
Transforming Growth Factor-beta (TGF-β) signaling plays a key role in tumorigenesis and tumor progression across various cancer types. In breast cancer, TGF-β signaling exhibits a dual role, functioning as a tumor suppressor in early stages but promoting tumor progression in advanced stages. Initially, TGF-β inhibits epithelial cell proliferation and induces apoptosis, exerting tumor-suppressive effects [249]. However, as breast cancer advances, cells often develop resistance to TGF-β's growth-inhibitory actions and exploit its pro-metastatic functions. This leads to the promotion of epithelial-mesenchymal transition (EMT), invasion, and metastasis, contributing to tumor aggressiveness. Similarly, in colorectal cancer (CRC), dysregulated TGF-β signaling is a hallmark of disease progression. Initially, TGF-β acts as a tumor suppressor by inhibiting epithelial cell proliferation and promoting apoptosis. However, during CRC progression, mutations often disrupt TGF-β signaling, abolishing its tumor-suppressive effects and activating pro-metastatic pathways [250]. Consequently, TGF-β promotes EMT, invasion, and metastasis, exacerbating tumor aggressiveness. In pancreatic cancer, dysregulated TGF-β signaling is frequently observed and associated with disease progression and metastasis. TGF-β promotes EMT, invasion, and metastasis in pancreatic tumors, while also stimulating the desmoplastic reaction and creating a tumor-promoting microenvironment. This dysregulation contributes to poor patient prognosis and therapeutic resistance [251]. Similarly, in lung cancer, TGF-β signaling exhibits complex roles. Initially acting as a tumor suppressor by inhibiting epithelial cell proliferation and inducing apoptosis, it later contributes to tumor aggressiveness as cancer cells acquire mutations that disrupt TGF-β signaling. This results in the promotion of EMT, invasion, and metastasis, ultimately leading to poor patient outcomes. In prostate cancer, dysregulated TGF-β signaling is implicated in disease progression and metastasis. TGF-β promotes EMT, invasion, and metastasis in prostate cancer cells, while also modulating the tumor microenvironment to support angiogenesis, immune evasion, and therapy resistance. This dysregulation contributes to tumor aggressiveness and metastatic spread in prostate cancer patients [252].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
Dysregulated expression of Transforming Growth Factor-beta (TGF-β) in hepatocellular carcinoma (HCC) can lead to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors [253]. TGF-β signaling serves as an inducer of epithelial-mesenchymal transition (EMT), prompting epithelial cells in HCC to lose their differentiated phenotype and acquire mesenchymal characteristics. This dysregulation triggers the loss of hepatocyte-specific features and the acquisition of mesenchymal traits, thereby increasing cellular plasticity and contributing to the emergence of heterogeneous cell populations within the tumor. Moreover, TGF-β signaling pathways can activate alternative differentiation programs in HCC cells by stimulating the expression of lineage-specific transcription factors and signaling molecules. This process drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells, thereby generating cellular heterogeneity within the tumor and potentially fueling tumor progression and therapeutic resistance [254]. Additionally, TGF-β is recognized for its ability to enhance cellular plasticity by promoting stemness and dedifferentiation across various cell types. In HCC, dysregulated expression of TGF-β may augment the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. Consequently, TGF-β-induced cellular plasticity may facilitate the emergence of therapy-resistant cell populations within the tumor microenvironment. Furthermore, TGF-β can modulate the tumor microenvironment by influencing the behavior of stromal cells, including fibroblasts, endothelial cells, and immune cells. This dysregulation alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations, thus contributing to the maintenance of tumor heterogeneity and promoting tumor progression [255]. Finally, TGF-β signaling pathways interact with other signaling pathways implicated in cell fate determination and differentiation, such as Wnt/β-catenin and Notch pathways. Dysregulated expression of TGF-β in HCC disrupts the balance of signaling pathways involved in maintaining hepatocyte identity and homeostasis, leading to the emergence of transdifferentiation and heterogeneity features. These interactions further exacerbate cellular plasticity and heterogeneity in HCC, contributing to tumor aggressiveness and progression [256, 257, 258].
16. Hippo signaling pathway
Expression in Other Cell-Types:
Hippo signaling pathway, originally recognized for its involvement in regulating organ size and tissue growth, is fundamental for the development and maintenance of various cell types beyond hepatocytes. In epithelial cells, the Hippo pathway governs processes such as proliferation, differentiation, and polarity [259]. Across different tissues like the skin, intestine, and lung, Hippo signaling orchestrates epithelial morphogenesis and ensures barrier function. Activation of the Hippo pathway represses genes associated with cell proliferation while promoting the establishment of apical-basal polarity, critical for the proper formation and sustenance of epithelial tissues. Furthermore, Hippo signaling exerts influence on mesenchymal cells, including fibroblasts, smooth muscle cells, and osteoblasts [260, 261]. During skeletal development, components of the Hippo pathway regulate the differentiation of mesenchymal stem cells into osteoblasts and chondrocytes, thereby contributing significantly to bone formation and remodeling. Additionally, Hippo signaling governs the contractility and migration of mesenchymal cells during tissue repair and organogenesis. In neural cells, Hippo signaling oversees neurogenesis, neuronal differentiation, and axon guidance within the developing nervous system. Particularly in the brain, components of the Hippo pathway control the proliferation and differentiation of neural progenitor cells, influencing cortical development and the formation of neuronal circuits [262]. Moreover, Hippo signaling modulates synaptic plasticity and dendritic arborization, both critical for proper neural circuit function. The Hippo pathway also participates in vascular development and angiogenesis, particularly concerning endothelial cells. By regulating endothelial cell proliferation, migration, and tube formation, Hippo signaling contributes to the genesis of new blood vessels during embryogenesis and tissue repair. However, dysregulated Hippo signaling can disrupt vascular morphogenesis and contribute to pathological angiogenesis, as seen in conditions like cancer and retinopathy [263]. Furthermore, Hippo signaling impacts the functionality of various immune cell types, encompassing T cells, B cells, and macrophages. Within the immune system, components of the Hippo pathway govern processes such as cell proliferation, differentiation, and cytokine production, thereby modulating immune responses and inflammation. Dysregulation of Hippo signaling has been associated with autoimmune diseases, cancer immunosuppression, and inflammatory disorders, highlighting its importance in immune regulation [264].
Presence or Role in Other Tumors:
The Hippo signaling pathway, renowned for its role in regulating organ size and tissue growth during development, is also deeply involved in various tumors. In liver cancer (Hepatocellular carcinoma - HCC), dysregulated Hippo signaling is a common occurrence. This pathway, crucial for liver organ size and function, undergoes disruption in HCC, leading to aberrant activation of YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif), downstream effectors [265]. Consequently, YAP/TAZ activation fosters hepatocyte proliferation, stemness, and resistance to apoptosis, thereby fueling HCC development and progression. Similarly, dysregulated Hippo signaling surfaces in breast cancer, contributing to its progression and metastasis. Abnormal YAP and TAZ activation in breast cancer cells promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), and metastasis, correlating with aggressive phenotypes and poor patient outcomes. Moreover, Hippo signaling dysregulation in breast cancer leads to therapy resistance, underscoring its potential as a therapeutic target. Colorectal cancer (CRC) also exhibits dysregulated Hippo signaling, impacting tumor initiation and advancement. The activation of YAP and TAZ promotes CRC cell proliferation, invasion, and metastasis, correlating with adverse clinicopathological characteristics and poor prognosis [266]. Furthermore, Hippo signaling modulation of the tumor microenvironment in CRC fosters angiogenesis, immune evasion, and therapy resistance. Likewise, in lung cancer, dysregulated Hippo signaling drives progression and metastasis. Aberrant YAP and TAZ activation in lung cancer cells fuel proliferation, EMT, invasion, and distant metastasis, aligning with aggressive tumor behavior and unfavorable patient outcomes. Moreover, dysregulated Hippo signaling contributes to therapy resistance in lung cancer, emphasizing its importance as a therapeutic target. In pancreatic cancer, dysregulated Hippo signaling promotes tumor progression and metastasis. Abnormal YAP and TAZ activation enhances pancreatic cancer cell proliferation, invasion, and metastasis to distant sites, correlating with poor prognosis and therapeutic resistance. Additionally, dysregulated Hippo signaling in pancreatic cancer shapes the tumor microenvironment, fostering desmoplasia and immune evasion [267].
Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:
Hippo pathway, crucial for regulating cell proliferation and apoptosis, is disrupted in HCC, leading to uncontrolled cell growth and tumor heterogeneity. This dysregulation results in varying levels of proliferation among different cells within the tumor, contributing to its heterogeneous nature. Furthermore, activation of the Hippo pathway, particularly through the downregulation of its effectors YAP and TAZ, inhibits stemness properties in hepatic stem cells. However, dysregulated Hippo signaling in HCC may induce stem-like characteristics in tumor cells, fostering a heterogeneous cell population with varying degrees of differentiation. Moreover, dysregulated Hippo signaling, leading to the activation of YAP and TAZ, is associated with the induction of EMT in cancer cells [268]. This process involves epithelial cells losing their characteristics and acquiring mesenchymal traits, resulting in increased migratory and invasive properties and further contributing to tumor heterogeneity. Additionally, dysregulated Hippo signaling influences cell fate decisions and plasticity within HCC tumors. In response to changes in the tumor microenvironment or therapeutic pressures, HCC cells with altered Hippo signaling may undergo phenotypic switching between hepatocyte-like and progenitor-like states, adding to the observed heterogeneity. Furthermore, the Hippo pathway not only affects tumor cell behavior but also shapes the tumor microenvironment [269]. Dysregulated Hippo signaling alters the crosstalk between tumor cells and stromal, immune, and vascular cells, leading to changes in the tumor microenvironment that contribute to tumor heterogeneity. Finally, the heterogeneity driven by dysregulated Hippo signaling can confer resistance to therapies. Subpopulations of cells with different Hippo pathway activity may respond differently to treatment, allowing for the survival and proliferation of resistant clones, further complicating therapeutic interventions [270].