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PMC10669128
Preclinical Models of Visceral Sarcomas
In particular, xenografts, such as mice injected with subcutaneous cell lines or PDXs, are commonly employed for STS studies.
PMC10669128
Preclinical Models of Visceral Sarcomas
For this purpose, immunocompromised mice are the most used models, although they might select for clones that do not fully represent the human neoplasm.
PMC10669128
Preclinical Models of Visceral Sarcomas
Xenografts have the advantage of allowing rapid compound efficacy screening and precise in vitro cell manipulation (e.g., gene overexpression or knock-down).
PMC10669128
Preclinical Models of Visceral Sarcomas
They can also produce a large number of tumors which can be isolated and analyzed.
PMC10669128
Preclinical Models of Visceral Sarcomas
Nonetheless, the most relevant drawback of xenografts is the lack of a reliable model of human tumor cell and mouse stroma interactions.
PMC10669128
Preclinical Models of Visceral Sarcomas
Another major issue is the fact that the animals are immunocompromised, hindering the immune system’s role in tumor growth, progression, metastasis, and response to therapy .
PMC10669128
Preclinical Models of Visceral Sarcomas
On the contrary, in a genetically engineered mouse, tumors arise in an authentic cancer microenvironment and, more importantly, the animal’s immune system remains intact .
PMC10669128
Preclinical Models of Visceral Sarcomas
Thus, compared to xenografts, GEMMs allow for a better replication of the interactions between tumor cells and the host microenvironment, allowing us to test mutation effects in a physiological context.
PMC10669128
Preclinical Models of Visceral Sarcomas
However, to generate and maintain GEM mice is expensive which, added to the complexity of results interpretation, leads to critical limitations .
PMC10669128
Preclinical Models of Visceral Sarcomas
In the field of sarcoma research, non-murine models, such as genetically modified zebrafish, have also been developed, but they primarily concern rhabdomyosarcomas, Ewing’s sarcoma, malignant peripheral nerve sheath tumors, chordomas , and, to the best of our knowledge, only one liposarcoma case .
PMC10669128
Preclinical Models of Visceral Sarcomas
Visceral sarcomas are generally investigated after the completion of the transformation process.
PMC10669128
Preclinical Models of Visceral Sarcomas
Hence, there is a compelling need to establish robust preclinical models that can faithfully replicate sarcomagenesis in vitro and in vivo.
PMC10669128
Preclinical Models of Visceral Sarcomas
Simultaneously, the need to discover new potential targets for personalized therapies is increasingly relevant.
PMC10669128
Preclinical Models of Visceral Sarcomas
This requires the establishment of reliable and predictive sarcoma models of patient response, to test only the most promising therapeutic approaches in clinical trials.
PMC10669128
Preclinical Models of Visceral Sarcomas
Future research should define the specific phenotype of cancer cells at the origin of different sarcoma histotypes and elucidate the mechanisms driving their transformation.
PMC10669128
Preclinical Models of Visceral Sarcomas
In this regard, a valuable research tool is represented by induced pluripotent stem cells.
PMC10669128
Preclinical Models of Visceral Sarcomas
This model has already been effectively applied in the field of genetic and oncological diseases, thanks to its capability to reproduce disease phenotypes within the appropriate cellular lineage .
PMC10669128
Preclinical Models of Visceral Sarcomas
The ability to derive tissue-specific isogenic iPSC lines, modified via genome editing at the level of driver oncogenes, would allow us to mimic different sarcoma subtypes in vitro.
PMC10669128
Preclinical Models of Visceral Sarcomas
iPSCs, along with three-dimensional cellular systems, might overcome the issues associated with the use of animal models and the limitations of the 2D cultures discussed in this review.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
•Enhanced glycolysis in GIST is an important metabolic feature.•GLUT play a significant role in GIST progression and response to treatment.•Glycolysis can lead to the therapeutic strategies for GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Enhanced glycolysis in GIST is an important metabolic feature.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GLUT play a significant role in GIST progression and response to treatment.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Glycolysis can lead to the therapeutic strategies for GIST.Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GIST primarily develops due to the constitutive activation of the receptor tyrosine kinase KIT or PDGFRA, with approximately 75 % of GISTs harboring gain-of-function mutations in KIT .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Surgical resection is the primary treatment option for GISTs that can be removed.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, for GISTs that are unresectable, metastatic, or recurrent, KIT inhibitors, such as imatinib mesylate (also known as imatinib), are administered [, , ].
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Drug resistance represents a major obstacle to the treatment of GISTs.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Typically, resistance to imatinib develops after a median duration of 18–24 months of therapy .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
While sunitinib and regorafenib are considered effective for treating imatinib-resistant GIST, the median progression-free survival is 8.5 months for sunitinib and 4.8 months for regorafenib [, , ].
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
A recent study has highlighted the potential of TAS-116, a heat shock protein 90 inhibitor, in the treatment of treatment-resistant advanced GISTs .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Nonetheless, only a few chemotherapy regimens are available for GIST, and no chemotherapy regimens are available for imatinib-resistant GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Tumor cells favor aerobic glycolysis, a phenomenon observed when sufficient oxygen is available.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
This pathway generates less energy than mitochondrial oxidative phosphorylation, which occurs in healthy cells.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Tumor cells facilitate nucleic acid synthesis and promote rapid growth using the pentose phosphate pathway .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Several studies have reported on the association between this distinct metabolic fingerprint and various hallmarks, including tumor cells’ progression and resistance to chemotherapy [, , ].
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In the context of GIST, there is a growing body of evidence suggesting that this cancer-specific metabolic paradigm influences tumor malignancy, tumor risk stratification, and resistance to imatinib [, , ].
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, the relationship between glycolysis and GIST remains unclear.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Here, we provide a brief overview and analysis of the role of glycolysis in GIST, laying special emphasis on potential avenues for metabolic research and underscoring its merit as an intriguing therapeutic target.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GLUT serves as the initial rate-limiting step in cellular glucose metabolism.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Within the GLUT family, GLUT-1 predominantly regulates basal glucose uptake, ensuring the maintenance of foundational cellular glucose metabolism.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Thus, this transporter is essential in the modulation of cellular energy production .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In the context of GIST, it has been demonstrated that elevated GLUT-1 expression corresponds to an increased tumor risk grade .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In a study assessing CD63 (a significant protein of the transmembrane 4 superfamily and an exosomal marker) expression in conjunction with GLUT-1 expression, a significant correlation was found between GLUT-1 expression and CD63 expression in tumor cells among 54 patients with CD117(c-kit)-positive gastric GIST who had not undergone prior treatment with imatinib or other chemotherapy agents, and high levels of GLUT-1 and CD63 were associated with a substantial decrease in disease-free survival .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Conversely, another study examining the characteristics of small extracellular vesicles derived from GIST cells in the plasma of patients with GIST suggested a correlation between an unfavorable prognosis and elevated carcinoembryonic antigen levels and/or diminished GLUT-1 levels .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Notably, direct comparisons between the expression levels of GLUT-1 and the levels of GLUT-1 in small extracellular vesicles may not be feasible, possibly accounting for the discrepancy observed in the abovementioned two studies .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Here, we conducted a comparative analysis between GIST cell lines with secondary mutations in PDGFRA exon 12 and the GIST-T1 cell line.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Interestingly, our findings revealed that imatinib treatment led to the downregulation of GLUT-1 and other components of the glycolysis pathway in parental GIST-T1 cells, even at low concentrations.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In contrast, imatinib treatment increased the expression of these components in imatinib-resistant cells .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Therefore, we considered that the glycolysis pathway is essential for the acquisition of imatinib resistance by GIST cells and for cell survival.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GLUT-2 is predominantly localized in pancreatic beta cells, hepatocytes, and renal tubular cells, whereas GLUT-3 is mainly expressed in nervous tissues .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In a study that assessed the potential advantages of continuous versus intermittent imatinib administration in mice implanted with an imatinib-resistant GIST cell line harboring a secondary mutation in KIT exon 17, cytoplasmic GLUT-2 expression was significantly elevated in the treated group compared with the untreated group.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Moreover, the cytoplasmic and membrane-bound GLUT-3 levels were significantly higher in the intermittent treatment group than in the continuous treatment group .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, the significance of these findings and their underlying mechanisms are yet to be fully elucidated.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GLUT-4 is a high-capacity glucose transporter primarily found in nondividing cells, such as those in adipose tissue, skeletal muscle, and the myocardium .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In a study conducted on 57 patients with GIST receiving neoadjuvant chemotherapy with imatinib, all patients exhibited detectable GLUT-4 levels before imatinib therapy.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, among 22 patients whose tumor samples were obtained during surgery after neoadjuvant chemotherapy, 19 showed decreased GLUT-4 expression .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Based on these data, imatinib was considered to interact with glycolysis and GLUT-4 expression.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Overall, these findings suggest that a multitude of GLUT subtypes are involved in the pathogenesis of imatinib resistance in GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The upregulation of GLUT expression can play a vital role in the acquisition of imatinib resistance by GIST and cell survival.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In addition to GLUT, hexokinase (HK), phosphofructokinase 1 (PFK1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), lactate dehydrogenase (LDH), and monocarboxylate transporters (MCT) are recognized to be associated with glycolysis .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
A previous study demonstrated increased activity of HK1 (one of the HK isoforms), PKM2 (one of the PK isoforms), and LDH in high-risk grade tumors, suggesting their potential in the preoperative prediction of malignancy .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Furthermore, research into the association between MCT and GIST has unveiled the pronounced expression of MCT1, MCT2, and MCT4 .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The coexpression of MCT1 and its chaperone, CD147, has been implicated in the aggressiveness of GIST and correlated with reduced patient survival .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
While numerous studies have reported on the association between glycolysis-related molecules and various types of cancer, there has been a paucity of research focusing solely on GIST [, , ].
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
A summary of glycolysis-related molecules in GIST is shown in Table 1.Table 1Role of glycolytic molecules in gastrointestinal stromal tumor.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Table 1MoleculesAssociations and functionsReferencesGLUT-1Elevated GLUT-1 expression corresponds to heightened tumor risk grade19GLUT-1 expression positively correlates with CD63 expression18High GLUT-1 and CD63 levels in GIST cells correlate with lower disease-free survival18High carcinoembryonic antigen or low GLUT-1 in plasma small extracellular vesicles indicates poor prognosis23Imatinib reduced GLUT-1 in GIST-T1 cells but increased glycolysis in imatinib-resistant cells20GLUT-2In imatinib-treated mice with resistant GIST, GLUT-2 expression was higher than in untreated mice25GLUT-3Intermittent imatinib treatment increased GLUT-3 levels compared to continuous treatment in mice25GLUT-4Neoadjuvant imatinib therapy reduced GLUT-4 expression27HK, PK, LDHHK1, PKM2, and LDH activity elevated in high-risk grade19MCTMCT1 and CD147 coexpression are associated with GIST aggressiveness and reduced patient survival29GIST: gastrointestinal stromal tumor; GLUT: glucose transporter; HK: hexokinase; LDH: lactate dehydrogenase; MCT: monocarboxylate transporters; PK: pyruvate kinase Role of glycolytic molecules in gastrointestinal stromal tumor.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
GIST: gastrointestinal stromal tumor; GLUT: glucose transporter; HK: hexokinase; LDH: lactate dehydrogenase; MCT: monocarboxylate transporters; PK: pyruvate kinase F-Fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is one of the most commonly used functional imaging modalities in clinical practice.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
This technique uses a radioisotope to trace glucose and is recommended for GIST imaging .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The imaging diagnosis using F-FDG PET/CT is based on glucose metabolism in vivo .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The accumulation of the tracer is primarily mediated by GLUT .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Notably, FDG PET/CT has been demonstrated to have a high predictive prognostic value for recurrence-free survival in patients with localized primary GIST through assessment of preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Regarding GIST patients with KIT exon 11 mutations, FDG PET/CT demonstrated that imatinib treatment reduces FDG uptake levels within 1–7 days post treatment .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Immunohistochemical findings have suggested the involvement of GLUT-4 in FDG uptake in GIST, which is confirmed by the decrease in GLUT-4 levels following imatinib therapy .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Additionally, in vitro treatment of GIST cells with imatinib caused translocation of GLUT-4 from the plasma membrane to the cytosol via endocytosis as shown by lower plasma membrane-bound GLUT-4 levels .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Imatinib directly affects glycolysis and GLUT-4 expression, thereby resulting in decreased FDG uptake .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
FDG uptake evaluations on preoperative PET/CT of 40 patients with GIST revealed positive correlations between FDG uptake and tumor size; tumor risk grade per the Fletcher classification; and GLUT-1, HK1, and LDHA expression levels .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Analyses were conducted on several metabolic parameters, including maximum standardized uptake value corrected for body weight (SUVbw), lean body mass (SUVlbm), and body surface area (SUVbsa), as well as MTV and TLG in 35 patients with GIST .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The study, which included 35 patients with GIST, aimed to assess the predictive capability of preoperative FDG PET/CT in determining the malignancy risk of GIST and the likelihood of recurrence and mortality.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Although there were no statistically significant associations between PET/CT metabolic parameters (SUVbw, SUVlbm, SUVbsa, MTV, and TLG) and patient demographics, tumor size, mitotic index, Ki-67, and tumor location, these parameters were positively correlated with the tumor risk grade per the Fletcher classification.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Moreover, MTV and TLG were identified as independent outcome predictors for progression-free survival .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The report of the aforementioned study suggests the profound involvement of molecules associated with glycolysis, including GLUT, in the risk of GIST malignancy and recurrence.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, the clinical utility of PET/CT in GIST remains unclear, and there is lack of direct evidence to show the extent of the effect of imatinib treatment on FDG uptake via downregulation of GLUT contributing to the risk of malignancy and recurrence of GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
A summary of FDG PET/CT in GIST is shown in Table 2.Table 2Overview of F-Fluorodeoxyglucose positron emission tomography/computed.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Table 2:Associations and functionsReferencesFDG PET/CT, using preoperative MTV and TLG assessments, strongly predicts RFS in localized primary GIST patients36Imatinib treatment lowers FDG uptake within 1–7 days27Imatinib downregulates glycolysis and GLUT-4 expression, leading to reduced FDG uptake27, 37FDG uptake positive correlates with tumor size, Fletcher risk grade, and the expression of GLUT-1, HK1, and LDHA19PET/CT metabolic parameters (SUVbw, SUVlbm, SUVbsa, MTV, and TLG) positive correlate with Fletcher risk grade but not with patient background, tumor size, mitotic index, Ki-67, or location38MTV and TLG independently predict PFS outcomes38FDG: F-Fluorodeoxyglucose; GIST: gastrointestinal stromal tumor; GLUT: glucose transporter; HK: hexokinase; LDHA: lactate dehydrogenase; MTV: metabolic tumor volume; PET/CT: positron emission tomography/computed tomography; PFS: progression-free survival; RFS: recurrence-free survival; SUVbsa: standardized uptake value corrected for body surface area; SUVbw: standardized uptake value corrected for body weight; SUVlbm: standardized uptake value corrected for lean body mass; TLG: total lesion glycolysis Overview of F-Fluorodeoxyglucose positron emission tomography/computed.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
FDG: F-Fluorodeoxyglucose; GIST: gastrointestinal stromal tumor; GLUT: glucose transporter; HK: hexokinase; LDHA: lactate dehydrogenase; MTV: metabolic tumor volume; PET/CT: positron emission tomography/computed tomography; PFS: progression-free survival; RFS: recurrence-free survival; SUVbsa: standardized uptake value corrected for body surface area; SUVbw: standardized uptake value corrected for body weight; SUVlbm: standardized uptake value corrected for lean body mass; TLG: total lesion glycolysis Using GIST cell lines, validation studies revealed differences in the metabolic activity of glycolysis and oxidative phosphorylation (OXPHOS) between imatinib-sensitive GIST and imatinib-resistant GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, these varied depending on the specific cell line examined.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
For instance, imatinib-resistant GIST 882 cells showed a distinct metabolic profile with increased levels of glycolysis and OXPHOS compared with their original parent cells.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In contrast, imatinib-resistant cells derived from the GIST-T1 cell line had glycolytic activity that was comparable to that of their parent cells; however, their mitochondrial respiration was decreased.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Moreover, imatinib-resistant GIST 882 cells were more vulnerable to glycolysis inhibition than GIST 882 cells, whereas imatinib-resistant GIST-T1 cells were more resistant to OXPHOS inhibition than GIST-T1 cells .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
The intertumor heterogeneity in the metabolic phenotype of imatinib-resistant GIST needs to further investigated.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Imatinib can influence the metabolic phenotype of GIST, potentially contributing to imatinib resistance.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
We also speculate that the observed differences in metabolic activity levels could be attributed to a process known as the reverse Warburg effect.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
In this mechanism, metabolites such as lactate and pyruvate are produced by oxidative stressed cancer-associated fibroblasts and are used by cancer cells for ATP synthesis within the mitochondria .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, no studies have confirmed the presence of this phenomenon in GIST.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Recent studies have highlighted the potential prognostic significance of various DNAs (KIT, PDGFRA, BRAF, SDH, SETD2, and ROR2) and microRNAs (miR-221, miR-222, miR-494, miR-196a, miR-320a, miR-218, miR-125a-5p, and miR-518a-5p) in GIST .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
However, only a few molecular markers have been developed for GIST prognosis.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
At present, there are no established circulating biomarkers associated with glycolysis .
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Fig. 1 illustrates the relationship among GIST, glycolysis, and oxidative phosphorylation.
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Fig. 1A schematic illustration of the relationship between gastrointestinal stromal tumor (GIST) and glycolysis and oxidative phosphorylation (OXPHS).
PMC11261875
Glycolysis in gastrointestinal stromal tumor: a brief overview
Particularly, we focused on the relationship bwtween GIST and imatinib, a representative drug for treating GIST.