Oxygen and metabolic reprogramming in the tumor microenvironment influences metastasis homing

Figures & data

Figure 1. In the tumor microenvironment, together metabolites and cellular oxygen partial pressure (PO₂) regulates different steps of metastasis. Where sufficient metabolites concentration favors the proliferation of cancer cells, their shortage induce the migration of cancer cells to metabolite and oxygen rich organs. Under the oxygen shortage metabolite rewiring maintains the viability of cancer cells, or even presence and absence of oxygen also regulates the metabolite rewiring of tumor microenvironment. During the cancer cell migration, altered metabolism and oxygen environment regulates autophagy for the maintenance of cancer cell metabolite requirement, immune evasion and resistance for anoikis to facilitate migratory behavior of cancer cells. Similarly cellular redox homeostasis maintains oxidative stress of cancer cells and vasculogenesis regulates the metabolites and oxygen shortage and also facilitate the migratory route of circulatory cancer cells. Additionally, altered oxygen and metabolism also maintains the drug resistance and dormancy in cancer cells followed by reoccurrence of cancer

Figure 2. Tumor microenvironment facilitate the proliferation and migration of cancer cells to pre-metastatic niche. Cancer microenvironment also maintains the plasticity and dormancy (G₀/G₁) in cancer cells. Physiological stress or drug environment induces the dormancy in cancer cells and dormant cancer cells initiate the growth of secondary tumor or reoccurrence of cancer

Figure 3. Healthy cells use a sequential regulated metabolism (glycolysis-TCA-oxidative phosphorylation and fatty acid oxidation) for energy generation and anabolic biosynthesis. But in cancer cells according to available nutrient and unfavorable surrounding they divert their sequential metabolism toward the altered metabolism. Under the oxygen limiting conditions cancer cells increase the cytosolic metabolism and reduce the mitochondrial oxidation

Table 1. Cancer metabolite rewiring regulator and their role in cancer metastasis

S No	Metabolism regulating enzyme	Metabolism	Role in metastasis	Cancer type
1.	Hexokinase	Aerobic glycolysis	Proliferation	Breast and hepatoma (Lincet et al., 2015)
2.	Pyruvate dehydrogenase kinase (PDK)		Proliferation, migration, autophagy, recurrence, drug and anoikis resistance	Glioma (Chae et al., 2016), nasopharyngeal carcinoma (Roh et al., 2016), breast (Dupuy et al., 2015) and colon (Lu et al., 2011)
3.	Phosphoglycerate mutase (PGAM)		proliferation	Lung (Li et al. 2006) and hepatoma (Ren et al. 2010)
4.	Lactate dehydrogenase (LDH)		Proliferation, immune evasion, autophagy, migration, drug resistance, and cancer recurrence	Pancreatic, breast, colon and NSCLC (Zhao et al., 2013), bladder (Zhao et al., 2015)
5.	Phosphofructokinase-1 (PFK-1)		Proliferation and migration	Breast, colon, ovarian (Lincet et al., 2015, Yi et al., 2012) prostate, lung, liver, colon and cervical (Yi et al., 2012)
6.	Pyruvate kinase M2 (PKM2)		Proliferation, drug resistance	Leukemia and colon (Schell et al., 2014)
7.	Pyruvate carboxylase (PC)	TCA cycle	Proliferation, migration, autophagy and drug resistance	Breast (Christen et al. 2016), colon, lymphoma and melanoma (Leone et al., 2019)
8.	Isocitrate dehydrogenase (IDH)		EMT	Glioblastoma and leukemia (Grassian et al., 2012)
9.	Glutamate dehydrogenase (GDH)	Amino acid metabolism	Proliferation, migration and drug resistance	Neuroblastoma (Quing et al. 2012), lung and breast (Jin et al., 2015)
10.	Asparagine synthetase		EMT, vasculogenesis, migration and colonization	Breast (Knott et al., 2018) and lung (Gwinn et al., 2018)
11.	Glutamate-oxaloacetate transaminase (GOT)		Proliferation, migration	Neuroblastoma (Quing et al., 2012)
12.	Glutamine synthetase (GS)		Proliferation, survival and vasculogenesis	Hepatocellular carcinoma (Adebayo Michael et al., 2019)
13.	Glutaminase (GLS)		Proliferation, migration, autophagy, angiogenesis and cancer cell survival	Colon, lymphoma, melanoma (Leone et al., 2019) and breast (Morotti et al., 2021), lung (Jiang et al., 2017)
14.	Acetyl-CoA carboxylase (ACC)	Fatty acid metabolism	Proliferation, migration and colonization	Breast (Garcia et al., 2017)
15.	ATP citrate lyase (ACLY)		Proliferation, migration, reoccurrence	Renal (Teng et al. 2018) and lung (Migita et al. 2008)
16.	Stearoyl-CoA desaturase-1 (SCD-1)		Stemness, migration, cell colonization and redox homeostasis	Colon cancer, glioblastoma (Choi et al., 2019)
17.	Acetyl-CoA acetyltransferase (ACAT)		Proliferation, migration and colonization	Prostate, lung, leukemia and breast (Fan et al., 2016)
18.	Acyl-CoA synthetase (ACS)		Proliferation, migration, dormancy	Lung (Padanad et al., 2016)
19.	Carnitine palmitoyltransferase-1 (CPT1)		Vasculogenesis, autophagy and dormancy	Breast (Park et al., 2016) and colon (Wen et al., 2017)
20.	Glutathione peroxidase (GPx)	Redox homeostasis	Proliferation, migration, and drug resistance,	Lung, breast (Jin et al., 2015) and pancreatic cancer (Meng et al., 2018)
21.	Glucose-6-phosphate dehydrogenase (G6PD)	Pentose phosphate pathway	Proliferation, migration, redox homeostasis, anoikis resistance	Breast (Sousa et al., 2020)