Patofyziologie

Pretreatment with a DNA methyl transferase inhibitor (DNMTi), 5-azacytidine (5-aza)

• Increases 5-hmC levels
• Via enhanced levels of TET family enzymes, most notably TET2
• Subsequently restores chemosensitivity both in vitro and in vivo in an animal model of aggressive platinum-resistant disease
• 5-hmC deficiency and intrinsic platinum resistance
• May benefit from pretreatment with DNMTis to enhance their chemosensitivity and achieve a more effective therapeutic response to standard chemotherapy

• Decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC
• Novel epigenetic marker in the diagnosis of HGSOC, as well at its ability to indicate long-term clinical outcome
• Loss of 5-hmC is correlated with
• Shorter time to relapse following platinum-based chemotherapy
• Poor prognosis in patients newly diagnosed with HGSOC
• Genetic rescue of low 5-hmC levels via TET2 overexpression restores platinum chemosensitivity
• Pretreatment with 5-azacytidine increases TET2 and TET3 expression in ovarian cancer cells

• aacrjournals.org/clincancerres/article/24/6/1389/456/Epigenetic-Reprogramming-Strategies-to-Reverse

Aldehyde Dehydrogenase Activity

• Underlying CSC therapy resistance
• By high ALDH activity and activation of developmental pathways
• Essential for embryonic development and tissue homeostasis
• Canonical Wnt/beta-catenin
• Notch and Hedgehog pathways
• Notch signaling contributes to survival and platinum resistance of ovarian CSCs
• Notch 3 expression
• Associated with poor prognosis for OC patients
• Hedgehog signaling
• Aberrantly activated in OC
• Affects cell growth, motility, invasion, and tumorigenesis
• Wnt/beta-catenin
• Involved in stem cell proliferation and differentiation
• CSCs of many tumors were found to overexpress beta-catenin
• Promotes stemness
• In OC, genetic mutations in the Wnt pathway
• Are rare
• Activation of Wnt signaling could be regulated by the tumor microenvironment
• Contributing to ovarian tumorigenesis
• www.frontiersin.org/articles/10.3389/fonc.2020.00319/full

BRCA 1/2 negative

• Connective tissue barrier prohibiting the interaction between the cancer and immune cells

• Inga-Maria Launonen, BM.

BRCA1/2

• Body's immune system is more effective against tumors with a mutation in BRCA1/2 genes
• In cca 20% of poorly differentiated serous carcinomas
• Most common form of ovarian cancer

• Killer T-cells closely guarded the aggressive tumour cells
• Particularly in tumours with BRCA1/2 mutations
• These patients had a markedly better prognosis.
• www.sciencedaily.com/releases/2022/02/220211102631.htm

Reduced concentrations in OC

Antioxidants

Lowered apoptosis in ovarian cancer tissues

Increased nitrosylation of caspase-3

• Significant reduction in the activity of caspase-3 in ovarian tumors

Elevated in ovarian cancer

Interleukin-6 (IL-6)

Akt

lysophosphatidyl acid (LPA)

• LPA is identified to elevate IL-6, IL-8 and VEGF through Akt/ nuclear factor kappa B (NF-kB) pathway in ovarian cancer cells

Protein kinase C (PKC)

• Modulatory role in a large number of signal transduction pathways
• Impairment in PKC function has been observed in
• Tumorogenesis
• Drug-resistance related to ovarian cancer

Prostaglandins levels are greater in ovarian tumors than normal cells

• Stimulate the invasion of cancer cells

Greater levels of oxidative stress than healthy women

Epithelial tissues of ovarian cancer exert a pro-oxidant condition

• Elevated expression of pro-oxidant enzymes
• Reduced expression of antioxidant enzymes

Elevated expression of inducible nitric oxide synthase (iNOS)

Myeloperoxidase (MPO),

• Enhances the production of NO from iNOS
• Elevation in MPO levels of ovarian cancer cells
• MPO also has key roles in the regulation of apoptosis
• Immune surveillance mechanisms
• 3-nitrotyrosine formation
• Inflammatory responses
• Source of free iron promotes oxidative stress - (ROS) generation
• Iron reacts with hydrogen peroxide (H2O2)
• Increases ROS production
• Oxidative stress may play a key role in ovarian cancer maintenance and progression.

NAD(P) H oxidase

Nitric oxide (NO)

lncRNA CRNDE

• Strongly associated with ovarian cancer prognosis
• Essential role in ovarian cancer radiation resistance in our research
• www.hindawi.com/journals/jhe/2021/8556965/

Promoter methylation of the BRCA tumor suppressor genes

• Has been implicated in both ovarian and breast cancer malignancies
• aacrjournals.org/clincancerres/article/24/6/1389/456/Epigenetic-Reprogramming-Strategies-to-Reverse

Quiescent cancer cells

• Low ATP demand
• Live in a highly compromised microenvironments
• Low glucose and hypoxia
• For these cells, inhibition of OXPHOS is lethal as there is not sufficient glucose to compensate for the loss of ATP production
• Standard chemotherapy treatment is very effective at killing highly proliferative cells
• Quiescent cells survive
• Causing tumor regeneration and cancer reoccurrence
• OXPHOS inhibitors
• Effective at eliminating quiescent ovarian cancer cells in metabolically compromised microenvironments.
• www.mdpi.com/1422-0067/20/1/229

Spheroids - CSCs in asictes

• Significantly more active TCA cycle
• Than their 2-dimensional counterpart
• Depend on OXPHOS for ATP production
• In both quiescent and proliferative layers
• Increased OXPHOS in ovarian cancer cells
• Enhances IL-6 production
• Promotes cancer cell survival and proliferation
• Impairs responsiveness to chemotherapy
• Shortens progression-free survival of ovarian cancer patients
• CSCs - high metabolic plasticity prior to differentiation
• Increase in TCA cycle activity
• Ovarian CSCs have
• Active mitochondria
• Higher rates of OXPHOS
• More sensitive to OXPHOS inhibitors than non-CSC

• Survive in presence of OXPHOS inhibitors
• By upregulating glycolysis to meet their ATP demands
• Highly proliferating cancer cells
• Extraordinarily high ATP demand and adequate levels of oxygen and glucose
• www.mdpi.com/1422-0067/20/1/229