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On the last day before the holiday, I believe everyone is fidgeting, and don’t read the analysis of the brain-burning text.
Today I will talk about tumor metabolism
.
Another advertisement: The second post is our recruitment information.
We will post hairy crabs on National Day.
If you are not very satisfied with your current job or like to eat hairy crabs, remember to pay attention to us.
Next time we will go fishing together in Yangcheng Lake
.
Not much to say today is a review of the latest progress in tumor metabolism published by Trends in cancer last month.
The author comes from Weill Cornell School of Medicine, Yale University School of Medicine, and the State University of New York at Stony Brook.
The team, they summarized the latest findings on the metabolism of rare melanoma cells, and proposed the use of cancer metabolism to improve treatment options for patients with rare melanoma
.
Research background: (1) Melanoma originates from the abnormal growth of melanocytes, and is classified into cutaneous melanoma (CM), uveal melanoma (UM), and mucosal melanoma according to the location of the primary tumor.
mucosal melanoma, MM) and acral melanoma (AM)
.
(2) Through the use of BRAF and MEK inhibitors and immune checkpoint antibodies, effective treatment of CM can be achieved, but it is not suitable for rare melanomas.
Therefore, it is necessary to design new programs to treat patients with rare melanomas
.
Figure 1.
Characteristics of rare melanoma (3) Reprogrammed cell metabolism contributes to cancer progression
.
By reprogramming metabolism, cancer cells can meet increased bioenergy and biosynthetic requirements and maintain redox balance
.
Targeting this process is an emerging treatment strategy
.
(4) There are metabolic differences between normal melanoma cells and rare melanoma cells (Figure 2, 3)
.
Some metabolic changes are the result of oncogene activation and/or tumor suppressor inactivation.
For example, KIT mutations are more common in AM (~36%) and MM (~25%) than in CM (~10%), and in KIT In the mutant melanocytes, hypoxia induces accelerated activation of the Ras/Raf/MAPK pathway, which promotes proliferation and transformation (Figure 2)
.
KIT mutation is also related to the increased utilization of glucose by MM cells.
In addition, MM showed increased expression of p53 (Figure 2).
Abnormal levels of p53 are related to the remodeling of cancer cell metabolism
.
Figure 2.
Overview of cell metabolism in mucosal melanoma (MM) Figure 3.
Overview of cell metabolism in uveal melanoma (UM) 1.
Uveal melanoma (UM): the most common eye cancer in adults, about 50% of UM patients will It develops into a highly aggressive tumor
.
The activating mutation of the gene (GNAQ/GNA11) in the G protein-coupled receptor pathway is considered to be the initiating factor of UM, and the inactivating mutation of BRCA1-related protein 1 (BAP1) is associated with UM metastasis
.
1.
The metabolism of normal choroidal melanocytes (NCM) and UM: (1) Under hypoxic conditions that simulate normal physiological oxygen conditions (3% oxygen), NCM cells are better than traditional tissue culture conditions (21% oxygen).
) Grow faster, while UM cells grow slowly under hypoxic conditions
.
(2) Compared with NCM, the expression of genes related to nutrient storage in UM cells is up-regulated, and the expression of genes related to different metabolic processes is different
.
(3) The NCM secretion group has higher amino acid/peptide and glycogen metabolism levels than UM cells
.
(4) The level of nuclear vitamin D receptor (VDR) in UM cells is significantly lower than that in NCM cells
.
2.
Glucose metabolism and insulin resistance: (1) UM cells seem to have higher glucose utilization; (2) down-regulation of glycogen metabolism may be a specific metabolic feature of UM relative to other cancer types, which may contribute to UM (3) Compared with healthy individuals, UM patients exhibit features of insulin resistance, including higher serum insulin and fasting blood glucose levels, and lower adiponectin levels
.
In addition, the level of adiponectin in patients with metastatic UM is much lower than that in patients with non-metastatic UM
.
All these indicate that UM is closely related to insulin resistance metabolism
.
3.
Mitochondrial metabolism: (1) UM is related to changes in mitochondrial metabolism including TCA cycle; (2) histone variant macroH2A1 is more highly expressed in metastatic UM than non-metastatic UM, and plays a key role in UM mitochondrial metabolism
.
In addition, compared with non-metastatic UM tumors, metastatic UM tumors show up-regulation of the expression of these genes, highlighting the potential link between increased mitochondrial metabolism and metastasis
.
(3) Mitochondrial metabolic reprogramming may play a role in UM metastasis
.
4.
Amino acid and lipid metabolism: (1) Compared with non-metastatic UM tumors, metastatic UM tumors involve amino acid metabolism (including d-arginine and d-ornithine) and lipid metabolism (including glycerolipids).
And fatty acid metabolism) increased gene expression, indicating that UM transfer is related to amino acid and lipid metabolism
.
(2) Changes in amino acid and lipid metabolism may promote the growth of circulating UM cells, thereby increasing the risk of metastasis
.
5.
Hypoxia and oxidative stress: (1) Under hypoxic conditions, tumor cells stabilize the expression of HIF1α protein, triggering changes in cell metabolism
.
In monomeric 3 UM tumors, hif1α-dependent metabolic remodeling may be heterogeneous and not dependent on oxygen levels, so it may induce different metastatic potentials
.
(2) Damage to the reactive oxygen species (ROS) scavenging system leads to oxidative stress, which plays a vital role in tumorigenesis and some eye diseases
.
Although little is known about the oxidative stress in UM cells and the defense mechanism against oxidative stress, studies have shown that in retinoblastoma, the level of ROS and the expression of ROS signal transduction-related genes are significantly increased
.
6.
The therapeutic potential of metabolic inhibitors in UM: (1) Studies have shown that based on OXPHOS gene markers, there is metabolic heterogeneity in bap1 mutant UM tumors
.
OXPHOS inhibitor significantly reduces the viability of UM cells
.
(2) Targeted cell metabolism can take advantage of the potential fragility and drug-resistant UM of UM, which may be a useful method to develop more effective UM treatments
.
2.
Mucosal melanoma (MM): The rarest subtype of melanoma (accounting for 1% of all cases), usually has a worse prognosis than CM
.
Compared with CM, MM single nucleotide mutation level is relatively low, but there are more chromosomal abnormalities and genomic DNA amplification
.
In MM (~25%), amplification of KIT sites is more common than in CM (~10%)
.
Due to the relatively limited research on melanoma subtypes and the lack of consistent results, it is difficult to evaluate the efficacy of targeted therapy and immunotherapy for MM
.
1.
Glucose metabolism: Increased glucose metabolism may be related to the decreased survival rate and increased aggressiveness of MM patients
.
2.
Mitochondrial metabolism: Mitochondrial defects may lead to abnormal mitochondrial metabolism, which is the basis for the metastasis and progression of MM tumors
.
Compared with CM, MM tissue has a higher mitochondrial content, which is related to the increased risk of oral MM lymph node metastasis
.
The expression of mitochondrial fission protein 1 (FIS1) and dynein-related protein 1 (DRP1) in oral MM was significantly increased, while sinus MM showed mitochondrial fusion protein 2 (MFN2) overexpression
.
In the late stage of oral and sinus MM, the expression of mitochondrial fission and fusion markers is higher
.
3.
Other metabolic processes: In oral MM, the process of adipogenesis may be up-regulated to promote tumor development and metastasis
.
Fatty acid synthase (FASN) is a de novo lipogenic enzyme, which has been overexpressed in many cancers
.
Compared with oral moles, the expression of FASN in oral MM was significantly up-regulated, but there was no significant difference with the degree of tumor invasion
.
3.
Acral melanoma (AM): A particularly aggressive subtype of melanoma with a very high 10-year mortality rate (88%), which is significantly higher than that of CM (68%)
.
Similar to MM, AM also exhibits different genetic characteristics compared to CM, including higher levels of chromosomal aberrations
.
The incidence of BRAF mutation (~35%) is lower than that of CM (~50%), but CCND1 genome amplification (~54% vs ~13%) and KIT mutation amplification (~36% vs ~10%) in AM More common
.
Currently, the FDA has not approved a treatment plan for AM patients
.
The low expression of AMPK-related kinase NUAK2 is associated with longer recurrence-free survival of AM patients.
The loss of NUAK2 reduces cell migration in vitro and the growth of melanoma tumors in vivo
.
AMPK-related kinases play a key role in cell metabolism
.
Whether metabolic changes are dependent on the expression of NUAK2 is unclear, but the results of the study indicate that significant changes in cellular metabolic function may be related to the progression and clinical outcome of AM
.
Article summary: The author reviewed recent studies and believes that the reprogramming of cell metabolism is a key determinant of tumor growth and metastasis in UM, MM, and AM
.
These new studies provide potential opportunities that can be used to design new treatments based on targeted inhibition of specific metabolic processes
.
However, further research is still necessary: (1) The main metabolites and pathways of the unique metabolic process of rare melanoma need to be described and defined, and detectable biomarkers are provided; (2) The effect of metabolic changes on rare melanoma The impact of tumor development and metastasis needs to be clarified, including the obvious liver tilt of UM; (3) The clinical effect of targeted metabolism to treat rare melanoma needs to be evaluated
.
Future research is expected to identify the new metabolic vulnerabilities of rare melanomas and eventually open up new treatment avenues for patients with rare melanomas
.
The editor is not easy to write, and it is friendly to copy, please contact the good-speaking editor butler at 15510012760 (same number on WeChat) for related questions about Shengxin: 18501230653 (same number on WeChat)
Today I will talk about tumor metabolism
.
Another advertisement: The second post is our recruitment information.
We will post hairy crabs on National Day.
If you are not very satisfied with your current job or like to eat hairy crabs, remember to pay attention to us.
Next time we will go fishing together in Yangcheng Lake
.
Not much to say today is a review of the latest progress in tumor metabolism published by Trends in cancer last month.
The author comes from Weill Cornell School of Medicine, Yale University School of Medicine, and the State University of New York at Stony Brook.
The team, they summarized the latest findings on the metabolism of rare melanoma cells, and proposed the use of cancer metabolism to improve treatment options for patients with rare melanoma
.
Research background: (1) Melanoma originates from the abnormal growth of melanocytes, and is classified into cutaneous melanoma (CM), uveal melanoma (UM), and mucosal melanoma according to the location of the primary tumor.
mucosal melanoma, MM) and acral melanoma (AM)
.
(2) Through the use of BRAF and MEK inhibitors and immune checkpoint antibodies, effective treatment of CM can be achieved, but it is not suitable for rare melanomas.
Therefore, it is necessary to design new programs to treat patients with rare melanomas
.
Figure 1.
Characteristics of rare melanoma (3) Reprogrammed cell metabolism contributes to cancer progression
.
By reprogramming metabolism, cancer cells can meet increased bioenergy and biosynthetic requirements and maintain redox balance
.
Targeting this process is an emerging treatment strategy
.
(4) There are metabolic differences between normal melanoma cells and rare melanoma cells (Figure 2, 3)
.
Some metabolic changes are the result of oncogene activation and/or tumor suppressor inactivation.
For example, KIT mutations are more common in AM (~36%) and MM (~25%) than in CM (~10%), and in KIT In the mutant melanocytes, hypoxia induces accelerated activation of the Ras/Raf/MAPK pathway, which promotes proliferation and transformation (Figure 2)
.
KIT mutation is also related to the increased utilization of glucose by MM cells.
In addition, MM showed increased expression of p53 (Figure 2).
Abnormal levels of p53 are related to the remodeling of cancer cell metabolism
.
Figure 2.
Overview of cell metabolism in mucosal melanoma (MM) Figure 3.
Overview of cell metabolism in uveal melanoma (UM) 1.
Uveal melanoma (UM): the most common eye cancer in adults, about 50% of UM patients will It develops into a highly aggressive tumor
.
The activating mutation of the gene (GNAQ/GNA11) in the G protein-coupled receptor pathway is considered to be the initiating factor of UM, and the inactivating mutation of BRCA1-related protein 1 (BAP1) is associated with UM metastasis
.
1.
The metabolism of normal choroidal melanocytes (NCM) and UM: (1) Under hypoxic conditions that simulate normal physiological oxygen conditions (3% oxygen), NCM cells are better than traditional tissue culture conditions (21% oxygen).
) Grow faster, while UM cells grow slowly under hypoxic conditions
.
(2) Compared with NCM, the expression of genes related to nutrient storage in UM cells is up-regulated, and the expression of genes related to different metabolic processes is different
.
(3) The NCM secretion group has higher amino acid/peptide and glycogen metabolism levels than UM cells
.
(4) The level of nuclear vitamin D receptor (VDR) in UM cells is significantly lower than that in NCM cells
.
2.
Glucose metabolism and insulin resistance: (1) UM cells seem to have higher glucose utilization; (2) down-regulation of glycogen metabolism may be a specific metabolic feature of UM relative to other cancer types, which may contribute to UM (3) Compared with healthy individuals, UM patients exhibit features of insulin resistance, including higher serum insulin and fasting blood glucose levels, and lower adiponectin levels
.
In addition, the level of adiponectin in patients with metastatic UM is much lower than that in patients with non-metastatic UM
.
All these indicate that UM is closely related to insulin resistance metabolism
.
3.
Mitochondrial metabolism: (1) UM is related to changes in mitochondrial metabolism including TCA cycle; (2) histone variant macroH2A1 is more highly expressed in metastatic UM than non-metastatic UM, and plays a key role in UM mitochondrial metabolism
.
In addition, compared with non-metastatic UM tumors, metastatic UM tumors show up-regulation of the expression of these genes, highlighting the potential link between increased mitochondrial metabolism and metastasis
.
(3) Mitochondrial metabolic reprogramming may play a role in UM metastasis
.
4.
Amino acid and lipid metabolism: (1) Compared with non-metastatic UM tumors, metastatic UM tumors involve amino acid metabolism (including d-arginine and d-ornithine) and lipid metabolism (including glycerolipids).
And fatty acid metabolism) increased gene expression, indicating that UM transfer is related to amino acid and lipid metabolism
.
(2) Changes in amino acid and lipid metabolism may promote the growth of circulating UM cells, thereby increasing the risk of metastasis
.
5.
Hypoxia and oxidative stress: (1) Under hypoxic conditions, tumor cells stabilize the expression of HIF1α protein, triggering changes in cell metabolism
.
In monomeric 3 UM tumors, hif1α-dependent metabolic remodeling may be heterogeneous and not dependent on oxygen levels, so it may induce different metastatic potentials
.
(2) Damage to the reactive oxygen species (ROS) scavenging system leads to oxidative stress, which plays a vital role in tumorigenesis and some eye diseases
.
Although little is known about the oxidative stress in UM cells and the defense mechanism against oxidative stress, studies have shown that in retinoblastoma, the level of ROS and the expression of ROS signal transduction-related genes are significantly increased
.
6.
The therapeutic potential of metabolic inhibitors in UM: (1) Studies have shown that based on OXPHOS gene markers, there is metabolic heterogeneity in bap1 mutant UM tumors
.
OXPHOS inhibitor significantly reduces the viability of UM cells
.
(2) Targeted cell metabolism can take advantage of the potential fragility and drug-resistant UM of UM, which may be a useful method to develop more effective UM treatments
.
2.
Mucosal melanoma (MM): The rarest subtype of melanoma (accounting for 1% of all cases), usually has a worse prognosis than CM
.
Compared with CM, MM single nucleotide mutation level is relatively low, but there are more chromosomal abnormalities and genomic DNA amplification
.
In MM (~25%), amplification of KIT sites is more common than in CM (~10%)
.
Due to the relatively limited research on melanoma subtypes and the lack of consistent results, it is difficult to evaluate the efficacy of targeted therapy and immunotherapy for MM
.
1.
Glucose metabolism: Increased glucose metabolism may be related to the decreased survival rate and increased aggressiveness of MM patients
.
2.
Mitochondrial metabolism: Mitochondrial defects may lead to abnormal mitochondrial metabolism, which is the basis for the metastasis and progression of MM tumors
.
Compared with CM, MM tissue has a higher mitochondrial content, which is related to the increased risk of oral MM lymph node metastasis
.
The expression of mitochondrial fission protein 1 (FIS1) and dynein-related protein 1 (DRP1) in oral MM was significantly increased, while sinus MM showed mitochondrial fusion protein 2 (MFN2) overexpression
.
In the late stage of oral and sinus MM, the expression of mitochondrial fission and fusion markers is higher
.
3.
Other metabolic processes: In oral MM, the process of adipogenesis may be up-regulated to promote tumor development and metastasis
.
Fatty acid synthase (FASN) is a de novo lipogenic enzyme, which has been overexpressed in many cancers
.
Compared with oral moles, the expression of FASN in oral MM was significantly up-regulated, but there was no significant difference with the degree of tumor invasion
.
3.
Acral melanoma (AM): A particularly aggressive subtype of melanoma with a very high 10-year mortality rate (88%), which is significantly higher than that of CM (68%)
.
Similar to MM, AM also exhibits different genetic characteristics compared to CM, including higher levels of chromosomal aberrations
.
The incidence of BRAF mutation (~35%) is lower than that of CM (~50%), but CCND1 genome amplification (~54% vs ~13%) and KIT mutation amplification (~36% vs ~10%) in AM More common
.
Currently, the FDA has not approved a treatment plan for AM patients
.
The low expression of AMPK-related kinase NUAK2 is associated with longer recurrence-free survival of AM patients.
The loss of NUAK2 reduces cell migration in vitro and the growth of melanoma tumors in vivo
.
AMPK-related kinases play a key role in cell metabolism
.
Whether metabolic changes are dependent on the expression of NUAK2 is unclear, but the results of the study indicate that significant changes in cellular metabolic function may be related to the progression and clinical outcome of AM
.
Article summary: The author reviewed recent studies and believes that the reprogramming of cell metabolism is a key determinant of tumor growth and metastasis in UM, MM, and AM
.
These new studies provide potential opportunities that can be used to design new treatments based on targeted inhibition of specific metabolic processes
.
However, further research is still necessary: (1) The main metabolites and pathways of the unique metabolic process of rare melanoma need to be described and defined, and detectable biomarkers are provided; (2) The effect of metabolic changes on rare melanoma The impact of tumor development and metastasis needs to be clarified, including the obvious liver tilt of UM; (3) The clinical effect of targeted metabolism to treat rare melanoma needs to be evaluated
.
Future research is expected to identify the new metabolic vulnerabilities of rare melanomas and eventually open up new treatment avenues for patients with rare melanomas
.
The editor is not easy to write, and it is friendly to copy, please contact the good-speaking editor butler at 15510012760 (same number on WeChat) for related questions about Shengxin: 18501230653 (same number on WeChat)
