Table 2.
Summary of the role of prostaglandins in cancer. In red: cellular, molecular factors or treatments that promote the development of cancer. In blue: cellular, molecular factors or treatments that hinder tumor progression.
| Tissue/Organ | Type of Cancer and Scenario | Cellular-Molecular Factors/Therapeutics | Molecular/Cellular Effect | Physiological/Pathological Impact |
|---|---|---|---|---|
| Skin | Squamous | AKR1C3+ | PGD2 decrease. | Promotion of neovascularization |
| PGF2α increase | ||||
| 15d-PGJ2 | Inhibition of STAT-3 pathway | Reduction of cell growth | ||
| PGI2 increases | Higher 5-year survival rate | |||
| miR-31-5p increases | ACOX-1 decrease. | Increase of tumor migration and invasion | ||
| PGE2 increase | ||||
| PGE2 | PGE2 increase, larger stage | Possible biomarker of progression? | ||
| Non-melanoma | Apigenin | COX-2 and PGE1-EP1/EP2 decrease | Inhibition of neoplastic progression | |
| Piroxicam | COX-2 decrease | Useful in prevention | ||
| Melanoma | PGF2α | Blocking AAS action | Prevention of tumor apoptosis | |
| PGF2α antagonist | Inhibition of ASA blockade | Promotion of tumor apoptosis | ||
| Topical Melanotan II | Inhibition of COX-2 expression and PGE2 production | Inhibition of the migration, invasion, and colony-forming capability | ||
| Bones | Osteosarcoma | SND1 | Increase of PGE2 | Antitumor strategy using COX2 inhibitors. |
| Potential biomarker of the therapeutic strategies | ||||
| PGE2 | >EP1 pathway | Increase of proliferation and decrease of apoptosis of cells | ||
| 17-PT-PGE2 | ||||
| Lungs | CRTC1+/LKB1 cancer | CRTC1+/LKB1− | Activation of cAMP/CREB y PGE2 | Promotion of tumor development |
| Niflumic acid (NS-398) | PGE2 decrease | Hindrance of tumor development | ||
| Non-small cell cancer | miR-574-5p | Decrease of CUGBP1 and increase of mPGES-1 and PGE2 | Promotion of tumor development | |
| 15d-PGJ2 | Increase of ROS and activation of caspases | Increase of apoptosis | ||
| PGD2 | ||||
| mPGES-1 inhibitors | PGE2 decrease | Cancelation of miR-574-5p effects | ||
| MHC-II+ lung cancer | PGIs | Increase of T-CD4+ lymphocytes | Inhibition of tumor growth | |
| Primary lung tumors | ACSL3 | Increase of LPIAT1 activity | Prediction of poor patient survival. | |
| Anchorage-independent growth | ||||
| Lung squamous cell carcinoma | PGE2 | Activation of TNF-alpha-TRAF2-MMP-9 | Progression of lung cancer | |
| TNF-alpha | ||||
| General lung cancer | NSAIDs | Inhibition of COX enzymes | Smaller tumor size and fewer metastasis. | |
| Mammary gland | Breast cancer | AKR1C3+ | PGF2α- FP and Ki-67 increase | Increase of cell proliferation |
| AKR1C3 inhibitor | PGF2α decrease | Reduction of cell expansion | ||
| PGF2α-FP increase | Activation of ERK1/2-MAPK pathway and activation of NF-κB |
Increase of resistance to QT | ||
| FP inhibitor | Inhibition of ERK1/2-MAPK pathway | Reduction of resistance to QT | ||
| NF-kB inhibitor | Inhibition of NF-κB factor | |||
| 15d-PGJ2 | Activation of AKT-AP-1 pathway | Promotion of tumor expansion. | ||
| 15d-PGJ2 | Up-regulation of Snail and CXCL8 expression | Epithelial-to-mesenchymal transition (EMT). | ||
| Tumor-stroma interaction | ||||
| 8-iso-PGF2α | Serum non-invasive marker | Oxidative stress and subsequent damaging of DNA | ||
| C136S-PTEN (mutated) | Not affected by 15d-PGJ2 | Resistant? | ||
| DGLA * | Activation of caspases, PARP and COX-2 | Decrease of tumor migration and invasion. Greater efficacy of treatment with 5-fluouracil. | ||
| PGE2-EP2 increase | CD80 decrease on macrophages | Reduced macrophage polarization | ||
| PGESm-1 Knock out | PGE2-EP2 decrease and CD80 increase | Normal macrophage polarization | ||
| PGI2 increase | Shorter survival time | |||
| Ibuprofen | PGE2 decrease | Less tumor volume (dose-dependent), more mature macrophages, more CD-45+ T-lymphocytes, and fewer immature monocytes | ||
| Propanolol + Etodolac (Peri-QX) | Inhibition of STAT and EGR3 pathways | Less tumor dissemination, more NK lymphocytes, more B cells, fewer monocytes, and less IL-6. | ||
| Liver | HCC | Increase of stellate cells | COX2-PGE2-EP4 increase | Fewer regulatory T-lymphocytes, more MDSCs |
| SC-236 (COX-2 inhibitor) | Stellate cells ** decrease | Stop the spread of cancer | ||
| AH23848 (EP4 inhibitor) | ||||
| PGE2 | EP4-G-Adenylate increase and activation of cyclase-cAMP-kinase A-CREB pathway and oncogene MYC | Facilitation of tumor expansion | ||
| Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). | 2,5-dimethylcelecoxib (DMC). PD-L1 | Inhibition of microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 production | DMC combined with atezolizumab: more antitumor effect and stronger blockage of immunosuppression effect on PD-L1 | |
| Digestive system | Esophageal squamous cancer | ZIP5 inhibitor | Cyclin D1 decrease. COX-2 increase | Metastasis reduction |
| Gastric adenocarcinomas | H. pylori | COX-2 increase | Promotion of the onset of neoplasia | |
| NSAIDs | Inhibition of COX | Effective prophylaxis | ||
| PGD2 | PPARγ decrease | Slower growth | ||
| 15-PGDH | FOXP3 | Anti-tumor immunity | ||
| Adenoma | EP4 inhibitors | Inhibition of PI3K-AKT-mTOR and ERK1/2-MAPK pathways | Reduction of the number of new adenomas | |
| ASA as prophylactic (75–325 mg) | Fewer adenomas and lower mortality | |||
| Sulindac (15-PGDH knock-out) | Fewer new adenomas and more inflammatory lesions | |||
| Colorrectal cancer | COX2 | Inhibition of COX2 | Prevention of carcinogenesis. Increase in the survival rate. | |
| Risk of cardiovascular complications with prolonged treatment | ||||
| Targeting the TME | Downstream molecules of PGE2 signaling | Promising approach | ||
| PGF2α | Increased migration and invasion | |||
| 15d-PGJ2 | MYC modulation and telomerase inhibition | Increased rate of cell death | ||
| CRTC1 | Increase of CREB/AP-1, COX-2 and aaPGE2 | Promotion of tumor development | ||
| IP6 | Decrease of COX-2 and PGE2 | Hindrance of tumor development | ||
| NSAIDs | Reduction of tumor mass and metastasis | |||
| AAS (Stage III) | Lower mortality and relapses | |||
| AAS + Statins | PG decrease | |||
| PGF2β | Increase of EGR1 factor and prostaglandin synthase E enzyme | Promotion of tumor progression | ||
| PGF2β inhibitor | Decrease of EGR1 factor and prostaglandin synthase E enzyme | Hindrance of tumor progression | ||
| Tumor suppressor Knock-out. 15-PGDH | Increased resistance to ASA and celecoxib | |||
| PGM increase | Elevated levels: patients already diagnosed > patients with multiple adenomas > healthy controls. | Early diagnostic marker? | ||
| XRCC5 protein | p300 and COX-2 increase | Promotion of tumor progression | ||
| p300 inhibitor | COX-2 decrease | Hindrance of tumor progression | ||
| Pancreas | Pancreatic cancer | AAS | Not very useful, since they do not express COX-1. | |
| Celecoxib | COX-2 decrease | Possible adjuvant treatment for cisplatin + gemcitabine? | ||
| Vitamin D3 analogues: calcipotriol | PD-L1 upregulation | Decreased cancer-associated fibroblasts proliferation and migration. Reduced release of PGE2. | ||
| Kidney | Renal cancer | 15d-PGJ2 | Activation of caspases, and JNK and AKT kinases. Intracellular | Promotion of apoptosis |
| [Ca2+] increase | ||||
| COX-1 increase | Higher degree of malignancy | |||
| PGE2 increase | Not related to tumor size, Fuhrman grade, TNM stage or histological subtype. | |||
| Cadmium | Activation of cAMP/PKA II-COX2 pathway and N-Catherin expression | Mediated cell migration and invasion | ||
| Urinary system | Bladder cancer | |||
| Nervous system | Glioma | PGE2-EP2 | PKA-II and CREB increase | Increase of proliferation and decrease of survival |
| PGE2-EP4 | TDO decrease | Reduction of macrophage activation | ||
| PGD2 increases | Reduction of tumor proliferation | |||
| PGD2 decreases | Increase of tumor proliferation | |||
| 15d-PGJ2 | ROS and caspases increase | Increase of cell death | ||
| Neuroblastoma | ASA | COX-independent mechanism involving an increase in p21 and underphosphorylated hypo-pRb1. | Adjunctive therapeutic agent | |
| Retinoblastoma | MicroRNA-137 | Inhibition of COX-2/PGE2 | Suppression of proliferation and invasion | |
| Immune system | Multiple Myeloma | 15d-PGJ2 | ROS increase | Increase of angiogenesis and promotion of apoptosis |
| via PPARγ decrease | ||||
| Increased intake of omega-3 and omega-6 polyunsaturated fatty acids | PGE2 y PGE3 decrease | Reduction of tumor growth | ||
| Acute lymphoblastic leukemia (ALL) | Indomethacin | Avoid the stromal cells diminished p53-mediated killing. Blockage of the production of PGE2 |
Reduction of progression of ALL | |
| EP4 receptor | Increase of intracellular cAMP | Sensitizes human T-ALL cells to dexamethasone | ||
| PGE2 | ||||
| General Leukemia | Selenium supplements | Activation of PPARγ. Inhibition of STAT-5 and CITED2 | Apoptotic effect | |
| 15d-PGJ2 | Increase of ROS-NADPH oxidase. Activation TRAIL-JNK. Inhibition of AKT |
|||
| Lymphomas | PGE2 | Factor ZBTB46 decrease | Prevention of differentiation to cDC | |
| NS-398 | PGE2 decrease and cDC increase |
Tumor burden reduction | ||
| Endocrine tissues | Pituitary adenomas | COX1/2 PGE2 | Promotion of tumor progression | |
| Papillary thyroid cancer | 15d-PGJ2 | [Fe2+] intracellular and ROS increase | Promotion of tumor apoptosis | |
| COX2 and PGE2 | BRAF-mutated tumors promote PGE2 synthesis | Promotion of tumor progression | ||
| Prostate cancer | AKR1C3+ | Increase of PGF2α and activation of MAPK pathway. | Increase of proliferation and resistance to radiation therapy | |
| 17β-HSD | Inhibition of PPARγ | |||
| Androgen receptor antagonists, such as enzalutamide | Blockage of 17β-HSD | Indomethacin suppresses AKR1C3 and eliminates resistance | ||
| PGE2-EP1/EP2 | Activation of PI3K/AKT/mTOR and matriptase pathways | Increase of migration and invasion | ||
| CAY10404 and celecoxib | PGE2 decrease. Inhibition of PI3K/AKT/mTOR and matriptase pathways |
Decrease of migration and invasion | ||
| 15d-PGJ2 | Inhibition of AR | Tumor suppressor | ||
| COX-2 increase | PSA and Gleason increase | Poorer prognosis, more relapses, and poorer survival. | ||
| Endometrial cancer | PGF2α | More proliferation and migration | ||
| AKR1C3+ | Better overall survival Prognostic biomarker | |||
| PGJ2 | Reduction of proliferation | |||
| Ovary cancer | RGS10 decrease | COX-2 and PGE2 increase | More resistance to chemotherapy | |
| COX-1 *** increase | Early diagnostic biomarker? | |||
| COX-1 inhibitors ([18F]-Fluorine y [18F]-P6) | Trackers when performing a PET scan? | |||
| SC-560 | Increased chemosensitivity | |||
| Serous ovarian carcinoma | PGD2 | Marker of good prognosis | ||
| HPV serotype 16 infection | COX-2 increase | Related to the onset of cancer? | ||
| Cervical cancer | PGE2 receptor, EP3 | Modulation of uPAR expression | Negative prognosticator of cervical malignancy | |
| Other tissues | Sarcoma | GW627368X (EP4 inhibitor) | BAX and AIF increase. | Reduction of tumor volume and weight. Induction of apoptosis |
| MCL-1, BCL-2 and PGE2 decrease | ||||
| Fibroblasts | COX-2, PGE2, FGF and VEGF increase | Increase of angiogenesis and tumor spread | ||
| DAPS | FGF and VEGF decrease | Decrease of angiogenesis and tumor spread | ||
| Head and neck cancers | COX-2 | Various mechanisms | Protumorigenic effect. COX-2 selective inhibitors |
|
| Oral squamous carcinomas | COX-2 | Loss of E-cadherin expression | EMT and angiogenesis | |
| TME/Metastasis/Immune surveillance | All | COX-2. PGE2, ATP | Increased angiogenesis | Supply of O2 and nutrients. |
| Vitamin D | Decrease of cancer risk and favorable prognosis | Sensitivity to NSIAIDs targeting PGE2 | ||
| Breast cancer | CXCL8 | Activator of fibroblasts, | Tumor-stroma interaction in TME | |
| Liver cancer | 2,5-dimethylcelecoxib (DMC) | Promotion of HBV-related HCC immune TME | Combined immunotherapy with DMC and atezolizumab | |
| Pancreatic adenocarcinoma | EPHA2 | PTGS2 (COX-2) | Suppression of anti-tumor immunity | |
| PMN-MDSCs | Increase of FATP2 | Immunosuppressive activity | ||
| Intestinal tumor | Mesenchymal niche | PGE2-PTGER4-YAP signaling axis | Initiation of colorectal cancer | |
| Breast cancer | PGE2 | MMP1 increase | More brain metastases | |
| PGI2 | Stops its development | |||
| 15d-PGJ2 | Inhibition of MMP9 through PPARγ/HO-1 signaling pathway | Prevention and treatment of breast cancer and its metastasis | ||
| Prostate cancer | mPGES-1 | Accumulation of BM-MDSCs in lungs | Use of Selective mPGES-1 inhibitors | |
| Renal cancer | 15d-PGJ2 | MMP decrease | Reduction of invasiveness | |
| Melanoma | PGD2 | Lower number of metastasis | ||
| Melanoma and non-small cell lung cancer | COX1/2 inhibitors | Lower number of metastasis | ||
| Colorectal cancer | Etodolac + Propanolol | Lymphocytes NK increase | Reduction of tumor progression | |
| Immune System | Immune surveillance | Immune system reacts to many tumors. | Therapeutic weapon to eliminate tumor cells | |
| M-MDSC | Increase of NO | Suppression of adaptive immunity. | Inhibition of the PGE2/p50/NO |
* After inhibiting the enzyme delta-5-desaturase (whose function is to convert DGLA into arachidonic acid). ** Only in vitro assays. *** Although in cancer COX2 is usually increased, in this case there is a very striking increase in COX-1.