MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Zhoršující, vyvolávající a rizikové faktory

Enhanced Angs expression

  • Increase relapse and decrease survival time (Sallinen et al., 2010, 2014; Lin et al., 2011).
  • Ovarian carcinoma had higher Ang2 levels
    • Compared to those of patients with benign ovarian tumors
  • Increased Ang-2 levels (nad 2.7 ng/ml)
    • Biomarker for poor recurrence-free survival (Sallinen et al., 2010)
  • Expression levels of Ang-1 and Ang-2 were 26 and 44%
    • Higher in women with ovarian cancer than in normal women
  • Increased Ang-2 expression
    • Related to advanced stage and grade of cancer and relapse of ovarian cancer
  • Elevated Ang-2 expression is a predictor of poor OS and short PFS (Sallinen et al., 2014).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

CD146 expression in the membrane of ECs

  • Promotes the migration of ECs and angiogenesis
  • CD146 is an endothelial biomarker
  • Extracellular domain of CD146 directly interacts with VEGFR2
  • CD146 can promote angiogenesis (Yan et al., 2003).
  • CD146 promotes the migration of ECs and the formation of microvasculature
    • By enhancing VEGFR2 phosphorylation
    • Downstream signaling (AKT/p38 MAPKs/NF-kappaB) activation (Jiang et al., 2012)
  • Gene and protein levels of CD146 and VEGFRA
    • Increased in patients with EOC
      • Compared to those of non-cancer patients (Zhou et al., 2019).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Human telomerase reverse transcriptase (hTERT)

  • Highly expressed in over 80% of tumors
    • Including human epithelial ovarian cancer (EOC)
  • HTERT is up-regulated in EOC and promotes tumor progression
  • RIF1 as a novel hTERT promoter-binding protein in EOC cells
  • Role of RIF1 on tumorigenesis in vivo was detected by the xenograft model.
  • RIF1 knockdown
    • Suppressed the expression and promoter activity of hTERT
      • Consequently inhibited the growth and CSC-like traits of EOC cells
    • Inhibited tumorigenesis in xenograft model
  • RIF1 overexpression
    • Had the opposite effect
  • HTERT has been demonstrated to be a central regulator of multiple hallmarks of cancer
    • Proliferation, survival and cancer stem cells (CSC) traits
  • CSCs including the ovarian cancer stem cells
    • Play crucial roles in tumor promotion, recurrence, metastasis and other malignant characteristics of human cancers
  • HTERT is a potential biomarker and therapeutic target for EOC
  • RIF1 (replication timing regulatory factor 1)
    • Prominent role in telomere length regulation in yeasts
  • In mammalian cells, RIF1
    • Modulates pathway choice in DNA double-strand break (DSB) repair as well as replication timing regulation
    • Involved in embryonic stem cells (ESCs) self-renewal
    • Highly expressed in mouse embryonic stem cells
    • Upregulated in breast cancer tissues
  • RIF1 knockdown
    • Decreased cell growth
    • Increased cisplatin sensitivity of cervical cancer cells
  • RIF1 expression upregulated in EOC tissues
    • Closely correlated with clinical stage and prognosis of EOC patients
    • Binding at the promoter of hTERT in EOC cell lines
  • RIF1/hTERT signaling pathway could serve as a potential therapeutic target for EOC.
  • jeccr.biomedcentral.com/articles/10.1186/s13046-018-0854-8

IL-4, IL-10, and IL-13

IL-6

  • Most abundant cytokine in ascites
  • High levels predict worse progression-free survival in patients with advanced OC
  • High IL-6 and TNF-alpha
    • Subgroup of patients
    • Suggests an interaction between ascites IL-6 and TNF-alpha driving tumor progression and resistance to chemotherapy
    • Confirmed in patient-derived ascites
  • www.jci.org/articles/view/142677#SEC1

Lymphocytes

  • Major component of the TME
  • B lymphocytes and T lymphocytes

B lymphocytes

  • Accelerate tumor progression
  • Protumorigenic cytokines
  • Regulating the Th1: Th2 ratio (Quail and Joyce, 2013)

T lymphocytes

  • According to the cytokine environment, T cells differentiate into various subsets (Wang M. et al., 2017).
  • Mature T cells:

CD3+CD4+ = helper T cells (Th cells)

  • Cytokines that promote or inhibit inflammation
  • Th1
    • Pro-inflammatory cytokines
    • Assist CD3+CD8+ T cells in tumor rejection
  • Th2 cells
    • Release anti-inflammatory cytokines
    • Promote tumor progression (Joyce and Pollard, 2009; Quail and Joyce, 2013)

CD3+CD8+ T cells = cytotoxic T lymphocytes (CTLs)

  • Tumor rejection
  • Inflammatory cytokines
  • Cell lytic molecules such as perforin and granzyme
  • Specifically recognize and destroy pathogen-infected or malignant cells (Joyce and Pollard, 2009; Zhang and Bevan, 2011)

CD4+ Treg cells (CD4+CD25+Foxp3+)

  • In the thymus, Treg cells universally express Foxp3
    • 5–10% of CD4+ T cells
  • Responding to TCR and TGF-beta, Treg cells show suppression
  • Protect hosts against autoimmune diseases
  • Tumourigenic role mainly through immunosuppression monitoring (Lindau et al., 2013)

Secreting immunosuppressive molecules

  • IL-10,
  • IL-35,
  • TGFbeta
  • IL-10 and TGFbeta
    • Key mediators that limit antitumor immunity
    • Promote tumor progression (Facciabene et al., 2012)
    • Promote DC polarization to tolerogenic phenotypes

Treg cells secrete VEGF

  • Also an immunosuppressive molecule (Vignali et al., 2008)
  • Regulate the differentiation of DCs.

Treg cells induce the apoptosis of effector cells

  • Secreting granzyme B and perforin (Vignali et al., 2008)

Metabolic disruption regulated by Treg cells

  • Deplete the local level of IL-2
    • Causes effector cells to starve
      • Apoptosis of effector cells

expression of CD73 and CD39

  • Treg cells catalyze ATP to adenosine
    • Inhibits the function of effector T cells (Deaglio et al., 2007; Vignali et al., 2008)

CTLA-4 (cytotoxic T-lymphocyte antigen 4)

  • Expressed on Treg cells, and CD80 and CD86 are expressed on DCs
  • Treg cells induce DCs through CTLA4–CD80/CD86 interactions
    • Induces the release of IDO (indoleamine 2,3-dioxygenase)
      • Depletes essential tryptophan
        • Inhibits the function of effector T cells (Fallarino et al., 2003)

Treg cells depleting costimulatory molecules

inhibiting LAG3 (lymphocyte-activation gene 3)

    • Binds to MHC class II molecules (Vignali et al., 2008)

TLR (Toll-like receptor), GITR (glucocorticoid-induced TNF receptor), CTLA-4, and FR (folate receptor)

  • Directly or indirectly regulate the function of Treg cells
    • Pasare and Medzhitov, 2003; Callahan et al., 2010; de Aquino et al., 2015
  • TLR activation
    • Decreases the suppressive effect of Treg cells
      • Partially through IL-6

GITR, a costimulatory molecule

  • High expression level on Treg cells (Pasare and Medzhitov, 2003)
  • Anti-GITR mAb
    • Downregulates the inhibition of Treg cells

CTLA-4 and FR4

  • Expressed on Treg cells
  • Blocking CTLA-4 or deleting FR4
    • Inhibition of Treg cells decreased
    • Active Treg cells were depleted (Callahan et al., 2010).

Lymphocytes

  • Were correlated with clinical outcomes in ovarian cancer
  • Plasma cell and B cell infiltration impacted the prognosis of ovarian cancer.
  • CD138 and CD20
    • Are markers for plasma cells and mature B cells
  • Patients with high expression of CD138 and CD20
    • Were related to advanced tumor grade.
  • High expression of CD138
    • Was linked to worse OS and OCSS (ovarian cancer-specific survival).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Lynch II


Abundance of M2-type tumor-associated macrophages (TAMs)


Myeloid-derived suppressor cells (MDSCs)

  • Heterogeneous population of myeloid cells
  • Co-express the myeloid surface markers GR-1 and CD11b (Atretkhany and Drutskaya, 2016)
  • MDSCs consist of three phenotypes:
    • PMN-MDSC,
    • M-MDSC
    • Small group of cells that have myeloid colony-forming activity
      • Myeloid progenitors and precursors (Gabrilovich, 2017)
  • PMN-MDSCs are similar to neutrophils
    • Represent over 80% of MDSCs
  • M-MDSCs
    • Similar to monocyte (Gabrilovich, 2017)

MDSCs promote tumor progression by various mechanisms

  • Immune suppression (Ostrand-Rosenberg and Fenselau, 2018)
  • Mainly target T cells
  • Accelerate lymphocyte nutrient depletion (Rodriguez et al., 2004; Srivastava et al., 2010)

L-arginine and L-cysteine

  • Essential amino acids for T cell activation and function
  • MDSCs produce ARG1 and depletion of L-arginine
    • Through an ARG1-dependent manner (Rodriguez et al., 2004)
  • MDSCs also sequester L-cysteine (Srivastava et al., 2010)
    • Amount of zeta-chain in the TCR complex is downregulated
      • Proliferation of antigen-activated T cells is suppressed
  • MDSCs disturb lymphocyte trafficking and viability (Hanson et al., 2009; Sakuishi et al., 2011).

Galectin 9

  • Expressed in MDSCs
  • Binds to TIM3 on lymphocytes
    • Induces the apoptosis of T cells (Sakuishi et al., 2011)

MDSCs express ADAM17

  • Can decrease the L-selectin level on T cells
    • Limit T cell recruitment in lymph nodes (Hanson et al., 2009)

MDSCs promote Treg cell

  • Activation and expansion (Gabrilovich et al., 2012)
  • MDSCs stimulate CD4+ T cells to translate into induced Treg (iTreg) cells
  • Expand natural Treg (nTreg) cells
  • Processes are associated with
    • CD40-CD40L interactions,
    • IFN-gamma,
    • IL-10,
    • TGFebta

Stimulate the generation of oxidative stress

  • Oxidative stress is linked to ROS and RNS
  • Superoxide reacts with NO and generates PNT (peroxynitrite)
    • Nitrates T-cell receptors
      • Limits the response of antigen-MHC complexes
        • Suppressing T cells directly
  • PNT also nitrates T-cell-specific chemokines
    • Decreases the combination of antigenic peptides to MHC
      • Limits the migration of T cells (Molon et al., 2011)

MDSCs facilitate neovascularization

  • Hypoxia in tumors
    • Induces MDSCs to produce VEGF, FGF2 and MMP9
  • Activation of STAT3 in MDSCs
    • Also stimulates neovascularization through IL-1beta, CCL2 and CXCL2 release (Bruno et al., 2019)
  • Stimulate invasion and metastasis by producing MMPs (Ostrand-Rosenberg and Fenselau, 2018).
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Activation of NF-kappaB

  • A protein complex
  • Not favorable in cancer treatment
  • Leads to cellular events that promote inflammation, cell proliferation, angiogenesis, metastasis, and discourages cell death.
  • NF-kappaB is associated with cancer risk, poor prognosis, and contributes to chemotherapy resistance. (Lee, Jeon et al. 2007; Sethi, Sung et al. 2008)
  • pinestreetfoundation.org/ovarian-cancer-chemotherapy-antioxidants/

Stress-induced phosphoprotein 1 (STIP-1)

Tumor fibroblasts differentiate from mesenchymal-derived cells

  • Fibroblasts in the tumor milieu = “CAFs” (Carcinoma associated fibroblasts)
  • CAFs are a crucial cell population in the tumor microenvironment
  • Part of the TME (Ishii et al., 2016), produce various
    • MMPs
    • Tissue inhibitor
    • Metalloproteinases (TIMPs)
    • proteins of ECM
      • Collagens,
      • Fibronectin
      • Laminin (Kalluri and Zeisberg, 2006; Erdogan and Webb, 2017)
  • Fibroblasts in the tumor milieu = “CAFs”
    • Can transdifferentiate from other cells
      • Pericytes,
      • Epithelial cells
      • ECs
  • Via exposure to
    • Platelet-derived growth factor (PDGF),
    • Tumor-derived transforming growth factor-beta (TGF-beta),
    • Vascular endothelial growth factor (VEGF),
    • Basic fibroblast growth factor (bFGF),
    • MMPs and reactive oxygen species (ROS)
  • %%h5(Cai et al., 2012; Yu Y. et al., 2014; Denton et al., 2018
  • CAFs are known to promote tumor progression
    • Enhance tumor cell proliferation, invasion and migration

Highly expressed CXCL14

  • Promoting cancer growth

Fibroblast activation protein alpha (FAP)

  • Enhanced the migration and invasion ability of HO-8910PM cells (a highly metastatic ovarian cancer cell line)
  • Increased HO-8910PM cell proliferation.

Increase the infiltration of FOXP3+ regulatory T lymphocytes (Tregs) at the tumor site

  • Immune suppression effect in the tumor milieu
  • CAFs promote immune inhibition and angiogenesis

High expression of stromal cell-derived factor-1 (SDF-1)

  • Released SDF-1 promotes
    • Angiogenesis
    • Tumor proliferation in a paracrine fashion (Orimo et al., 2005)

Overexpression of FAP

  • Increase platinum resistance and accelerate recurrence
    • Acted as a hallmark for platinum resistance
  • Patients with FAP+ stroma
    • Had a shortened recurrence compared to that of patients with FAP- stroma
  • Mhawech-Fauceglia et al., 2015
  • CAFs was a biomarker of poor prognosis in ovarian cancer
    • Yang et al., 2013; Mhawech-Fauceglia et al., 2015; Zhao et al., 2017; Givel et al., 2018

Expression of CXCL12beta + infiltration of CAF-S1 (a subtype of CAFs)

  • Implied a dismal prognosis in high-grade serous ovarian cancers (HGSOC) (Givel et al., 2018)

Different subtypes of CAFs

  • Heterogenous function status
  • Subsets distinguished by the FAP expression level

FAP-high CAF subtype

  • Aggressively enhance tumor progression
  • Negatively influence patient outcomes

VEGF

  • Indicate poor clinical outcomes (Wimberger et al., 2014; Shen et al., 2017; Sopo et al., 2019).
  • VEGFR1 expression
    • Was closely related to decreased overall survival (OS)
    • Progression-free survival (PFS) (Wimberger et al., 2014)
  • VEGFR1, VEGF-A and VEGF-D
    • Highly expressed in omental metastases
      • Compared to expression in primary ovarian epithelial tumors
  • Low VEGF-A expression
    • Were more likely to have a poor prognosis
  • High VEGF-C expression
    • Were related to a short PFS (Sopo et al., 2019).

Wnt signaling

  • The progressing tumor presented with molecular patterns of immune suppression
    • Associated with
      • Wnt signaling
      • Higher HLA mutation
      • Higher neoepitope loads

Positively selected CSCs by chemotherapy

Activation of TLR-4 by LPS / derivates

  • Drives macrophage polarization toward an M1 pro-inflammatory phenotype
  • TLR-4 agonists could be used
  • In vitro studies TLR-4 on ovarian cancer cells
    • Promotes cell proliferation and survival
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC6281979/

GLUTAMINE, LEUCINE, METHIONINE, AND TYROSINE + melphalan

Human ovarian cancer cells

Autophagy

  • Is required to
    • Maintain dormant human cancer cells in a nutrient-poor environment with a poor blood supply
  • In patients with ovarian cancer who have been treated with surgery and six rounds of chemotherapy
    • “second-look” operations can detect small deposits of cancer in at least 50% of patients who have a normal CT scan and CA125 level
  • In more than 80% of these patients with positive second-look operations
    • Persisting dormant drug-resistant cancer cells are undergoing autophagy
  • Inhibiting autophagy could starve these dormant cancer cells
  • ocrahope.org/project/targeting-dormant-ovarian-cancer-cells-peptide-inhibitors-autophagy/

BRCA 1 a 2

CD8/CD4 T-REG BUŇKY a SERÓZNÍ OVARIÁLNÍ KARCINOM

  • Ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells
    • Correlate with poor clinical outcome in human serous ovarian cancer
      • Preston CC. Plos 1, 2013

Skupina 52 pacientek s pokročilým stádiem serózního ovariálního karcinomu

  • 31 pacientek mělo dobrou dobu přežití ( > 60 měsíců)
  • 21 pacientek mělo krátkou dobu přežití (< 18 měsíců)
  • Poměr efektorů/supresorů
    • Může být mnohem důležitější faktor než samotné počty lmfocytárních buněk
    • By mohly být úspěšné imunoterapeutické strategie modifikující poměry CD4(+) / CD25(+) / FOXP3(+) T-reg buněk nebo CD4(+) / CD25(+) / FOXP3(-) T- buněk oproti efektorových CD8(+) buňkám.


Cu

  • Excessive levels of Cu have been associated with
    • Enhanced proliferation,
    • Angiogenesis,
    • Metastasis of cancer cells
  • Leading to cancer progression
  • Targeting Cu homeostasis has emerged as a novel strategy in the treatment of cancer
  • Li, 2020; Michniewicz et al., 2021
  • Metal binding drugs to form complexes with Cu to selectively target cancer cells
    • Bertolini et al., 2015; Saluja et al., 2018
  • Candidate is Disulfiram (DSF)
  • wlv.openrepository.com/bitstream/handle/2436/624908/Kannappan_Recent_advances_2021.pdf?sequence=3

Increased activation of the p38-MAPK pathway

Methyltransferase nicotinamide N-methyltransferase (NNMT)

Cholesterolová deplece v membránách TAMs

Increased Treg infiltration

Chloride intracellular channel protein 3 (CLIC3)

CAPG, LCK and TNFAIP6

CCNE1 +, BRCA -, recomb. - , ESR1-CCDC170 fusion +

  • HGSOC primary tumor samples
  • Association between short-term survival and
    • Copy number gain of CCNE1
    • Lack of BRCA mutation signature
    • Low homologous recombination deficiency scores
    • Presence of ESR1-CCDC170 gene fusion (Yang S. Y. C. et al., 2018)
  • www.frontiersin.org/articles/10.3389/fcell.2020.00758/full

Expression pattern of 22 matrisome genes


Dendritic cells (DCs)

  • Capture endogenous or exogenous antigens, process them, and present
  • Bridge connecting the innate and the adaptive immune system (Timmerman and Levy, 1999; Riboldi et al., 2005)
  • Two main subtypes of DCs:

Conventional DC (cDC)

  • Antigen presentation
  • Plasmacytoid DC (pDC)
    • Produces IFN upon antigen stimulation from activating lymphocytes and other myeloid cells (Labidi-Galy et al., 2011; Vu Manh et al., 2015)
  • 5–10% of myeloid cells in most tumors
  • Rare in mouse tumors but found in most human tumors (Tang et al., 2017).
  • Key roles in anti-tumor immunity
    • Indispensable for T cell immune responses against tumors (Casey et al., 2015)
  • Responsible for tumor antigen recognition
    • Initiating event of the tumor-specific adaptive immune response
  • DCs can sense damage-associated molecular patterns (DAMPs)
    • Released from dead cancer cells
      • Double-stranded DNA (dsDNA) fragments
      • Calreticulin
      • Endoplasmic reticulum (ER) chaperone
    • Eliciting Th1 polarized immunity (Ding et al., 2018; Kasikova et al., 2019).
  • DCs present peptides to CD4+ and CD8+ T cells
  • Initiate a series of T cell activity (Dudek et al., 2013; Sabado et al., 2017).
  • Significant for tumor development prevention (MacKie et al., 2003; Galon et al., 2006).
  • DCs are also crucial for:
    • Augmentation of cytotoxic T lymphocytes (CTLs) population in the TME
  • Intratumoral cDCs are responsible for intratumoral CTL proliferation
    • Both in vivo and in vitro (Diao et al., 2011)
  • The only group of phagocytosing tumor myeloid cells
    • That can stimulate CD8+ T cell proliferation (Broz et al., 2014)
  • Major determinant of success in tumor deterrent, from the immune aspect (Budhu et al., 2010)
    • Increase the functional tumor-infiltrated CTL population
  • Significance of cDCs in the TME for anti-tumor responses is self-evident.

Effective T cell activation by DCs require

  • DC maturation,
    • After DC exposing to antigen
      • Increased membrane expression of MHC and co-stimulatory molecules (CD80, CD86, CD40)
        • (Bol et al., 2016; Bhatia et al., 2019)
  • Alteration of chemokine receptors
    • To favor DC lymph node (LN) migration (Drakes and Stiff, 2018)

Mature DCs

  • Produce cytokines that favor Th1 (anti-tumor) immunity
  • Cohorts of HGSOC patients that tumor-infiltrated mature LAMP+ DCs
    • Is robustly associated with Th1 immune responses,
    • Clinically favorable cytotoxic activities in the TME and favorable OS.

DC maturation can be hampered by

  • Leaving DC immatured
    • Developing into a tolerogenic status and promote immune tolerance (Dhodapkar et al., 2001)
    • Immature DCs express low levels of co-stimulatory molecules and cytokines
  • Immune-modulating molecules in the TME, such as
    • IL-6,
    • IL-10
    • VEGF
    • Tumor-derived soluble mediators and exosomes
    • Activation of oncogene STAT3 in DCs
    • ER stress response
    • Abnormal intracellular lipid accumulation (Cubillos-Ruiz et al., 2015; Tang et al., 2017; DeVito et al., 2019)
  • These factors suppress DC functions
    • By reducing the expression of co-stimulatory molecules and the secretion of pro-inflammatory cytokines
    • Inhibiting DC lymph node chemotaxis
    • Dampening DC differentiation
    • Inducing tolerogenic phenotypes on DCs and shortening the lifespan of DCs (Tang et al., 2017).
  • Tolerogenic DCs
    • Suppresses anti-tumor immunity via several mechanisms
      • Produce less pro-inflammatory cytokines
      • Induce immune suppressive cytokines
  • 44 ovarian cancer patients
    • Intra-tumoural tolerogenic pDCs secreted fewer
      • IFN-alpha, TNF-alpha, IL-6,
      • Macrophage inflammatory protein-1beta
      • CCL5
    • ++induced IL-10 from CD4+ T cells++
      • Promoting immune tolerance in these patients
  • Harbor enzymes negatively regulating T effector cell functions
    • nitric oxide synthase (NOS)
    • Indoleamine 2,3-Dioxygenase (IDO)
      • Enzyme catalyzing tryptophan degradation
        • Capable of suppressing tumor-infiltrated lymphocyte proliferation
        • Promoting Treg differentiation
        • Inducing T cell anergy
        • Promoting tumor angiogenesis as well as metastasis (Munn et al., 2005; Tanizaki et al., 2014; Munn and Mellor, 2016)
  • Significantly increased frequency of IDO+ DCs in tumor
    • Draining LN compared to the normal donor LN
  • In vitro study revealed IDO significantly inhibited proliferation of tumor-associated lymphocytes derived from EOC patients (Qian et al., 2009).
  • Higher surface expression of B7-H4
    • A B7 family molecule
    • Correlated with higher mature DC (CD11c+HLA-DRhigh) infiltration in EOC patient
    • May be associated with increased expression of CXCL17, a monocyte and DC chemoattractant in those tumors
  • Tumour-to-stroma ratio (TSR)
    • Percentage of malignant cell component relative to the stroma in the tumor tissue
      • Impact on infiltrated DC phenotype
    • High TSR was associated with elevated PD-L1 expression on mature DCs (CD11c+HLA-DRhigh) infiltrating in ovarian tumor tissue (MacGregor et al., 2019b).
  • Ovarian cancer patients, tumor pDCs
    • Produced less pro-inflammatory cytokines than pDCs from ascites or peripheral blood.

Cancer mouse model

  • At the early stage
    • Tumor growth was prevented by infiltrating DCs
    • DC depletion at this stage accelerated tumor expansion
  • At the advanced stage
    • DCs become immunosuppressive in the TME
    • DC depletion at this stage significantly delayed disease progression
    • (Scarlett et al., 2012)

Mouse model of ovarian cancer

  • Progressively gained immunosuppressive phenotype of infiltrating DCs
    • As the tumor progressed over time
      • By gradually increased PD-1 expression.

Emodin

Endothelial cells (ECs)

  • Components of the TME
  • Lining the vessels
  • Crucial for transporting oxygen and nutrients
  • Associated with angiogenesis
  • (Carmeliet and Jain, 2000; Hanahan and Weinberg, 2011)

VEGF

  • VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PLGF (placental growth factor)

Receptors for VEGF

  • VEGF receptors 1 (VEGFR1),
  • VEGFR2
  • VEGFR3
  • VEGFR1 and VEGFR2
    • Mainly expressed on ECs and are receptors for VEGF-A (Hagberg et al., 2010)
  • VEGFR1
    • Is also a receptor for VEGF-B and PLGF
  • VEGFR3
    • Is a receptor for VEGF-C and VEGF-D

VEGF family

  • Implicated in the adjustment of angiogenesis and lymphangiogenesis
    • (Tammela and Alitalo, 2010; Apte et al., 2019)
  • VEGF-A
    • Is crucial for angiogenesis
  • VEGF-C and VEGF-D
    • Regulate lymphangiogenesis (Tammela and Alitalo, 2010; Apte et al., 2019)


Estrogenní látky

Potraviny

  • Nejvyššími zdroji přímo živočišných estrogenů ve stravě jsou
    • Mléko
    • Vejce

Obezita

  • Velký zdroj lidských estrogenů je tuková tkáň

Metabolity léků

  • Ani nemají estrogenu podobné struktury, ale mají estrogenní aktivitu
    • Biodegradací v půdě třeba i antiepileptika

Plísňové toxiny

Změkčovadla z plastů

Estrogeny z HAK v pitné vodě

Vliv střevního mikrobiomu


Farmakorezistence

  • Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway
  • Downstream factors of this pathway
    • MDR1
    • NF-kappaB
    • Closely related to the occurrence of drug resistance in cancer
  • Cisplatin resistance to OC
    • Was related to the PI3K/AKT/mTOR pathway
  • www.hindawi.com/journals/ecam/2016/4651949/

HML2 Env was detected on the surface of ovarian cancer (OC) lines and patients' cells, showing a general correlation with the tumor histotype (Wang-Johanning et al., 2007; Rycaj et al., 2015). OC patients showed significantly higher titers of Abs against HML2 Env and specific T-cell cytotoxicity against autologous OC cells (Wang-Johanning et al., 2007; Rycaj et al., 2015). However, the similar Ab positivity found against HERV-E and ERV3 Envs (Wang-Johanning et al., 2007) together with the general hypomethylation of HERV sequences in OC (Iramaneerat et al., 2011) suggest that the increased HERV expression and Ab production could constitute (at least in part) a tumor epiphenomenon. However, even HERV proteins arisen from tumor-dependent upregulation can then participate in a multifactorial stimulation, contributing to cancer progression.https://www.frontiersin.org/articles/10.3389/fmicb.2018.00462/full

IL-6, CCL2/MCP-1, and TNF-alpha

  • Ovarian cancer patients
  • Higher concentration of in?ammatory cytokines such as
    • IL-6, CCL2/MCP-1, and TNF-alpha
  • Important role in the disease’s genesis and progression
  • These cytokines feed a negative cycle by attracting and stimulating cytokine-producing cells, which then enhance their protumorigenic function even more (Gastl and Plante, 2000; Maccio et al., 2021)
  • www.readcube.com/articles/10.3389/fphar.2022.987088

Immune checkpoint blockade therapies

Imunitní buňky v ascitu po chemoterapii

Kyselina listová

  • Folate receptor is overexpressed on the vast majority of cancer tissues
    • Expression is limited in healthy tissues and organs
    • Highly expressed in epithelial, ovarian, cervical, breast, lung, kidney, colorectal and brain tumors
  • d-nb.info/1097812596/34

Macrophages

  • Essential population of immune cells
  • Participate in inflammation and tumourigenesis

Tumor-associated macrophages (TAMs)

  • Derive from
    • Resident macrophages
    • Infiltrating macrophages from bone marrow monocytes circulating in the blood
(Ghosn et al., 2010).
  • TAMs can present two main phenotypes:
    • The anti-tumor M1 macrophages
    • Pro-tumor M2 macrophages
  • (Sica et al., 2008; Grivennikov et al., 2010; Qian and Pollard, 2010; Sica, 2010; Gupta et al., 2018)

Stimulated na M1

  • Interferon-gamma (IFN-gamma)
  • Bacterial lipopolysaccharide (LPS)
  • Granulocyte-macrophage-colony-stimulating factor (GM-CSF)
  • Monocytes differentiated into M1 macrophages
    • Can secrete IL-1, IL-12, TNFalpha and CXCL12
  • (Sica et al., 2008; Ramanathan and Jagannathan, 2014)
  • M1 macrophages possess
    • Cytotoxicity,
    • Tumor suppression
    • Immune-stimulation functions (Galdiero et al., 2013).

Stimulated na M2

  • By IL-4, IL-10, and IL-13
  • (Leyva-Illades et al., 2012; van Dalen et al., 2018)
  • Immune escape tumor macroenvironment
  • Immunosuppression due to the secretion
    • IL-4 and IL-13, by cancer cells
  • Accelerates monocytes to M2 macrophages
  • M2 macrophages, in turn, can promote tumor growth (Gordon, 2003; Roy and Li, 2016)

In ovarian cancer, TAMs are predominantly M2 macrophages, associating with tumor invasion, angiogenesis, metastatic disease and early recurrence (Pollard, 2004; Reinartz et al., 2014; Yin et al., 2016). They produce and secrete cytokines, which have immunosuppressive effects, such as IL-1R decoy, IL-10, CCL17 and CCL22 (Gordon, 2003). Via several mechanisms, they suppress adaptive immunity (Li et al., 2007; Noy and Pollard, 2014). Firstly, M2 macrophages can inhibit the proliferation of T cells and accelerate the immunosuppression of Treg cell transport to tumors by producing the chemokine CCL22 (Li et al., 2007). Secondly, M2 macrophages express the ligand receptors for CTLA-4 and PD-1. The activation of PD-1 and CTLA-4 inhibits cytotoxic function and regulates the cell cycle of T cells (Noy and Pollard, 2014). Then, M2 macrophages can also inhibit the activation of T cells through the depletion of L-arginine, which plays an essential role in T cell function (Galdiero et al., 2013). Arginase I (ARG1), a hallmark of M2 macrophages, is an L-arginine processing enzyme. In the TME, ARG1 decomposes L-arginine into L-ornithine and urea. The depletion of L-arginine suppresses the re-expression of the CD3 ? chain, which is internalized by antigen stimulation and T cell receptor (TCR) signaling (Rodriguez et al., 2004).
Aside from immune suppression, M2 macrophages also take part in tissue repair, ECM remodeling and angiogenesis, which are processes involved in tumor progression as well (Mantovani et al., 2002; Coffelt et al., 2010; Ruffell et al., 2012; Finkernagel et al., 2016; Roy and Li, 2016). They can restructure ECM and regulate ECM components by degrading ECM via producing MMPs, serine proteases and cathepsins (Ruffell et al., 2012), which may facilitate tumor cell migration, invasion and metastasis. Additionally, they can secrete VEGF-A, which is an angiogenic factor, and produce proangiogenic cytokines, such as IL-1ß, TNFalpha and uPA (urokinase-type plasminogen activator) (Roy and Li, 2016). In M2 macrophages, there is a subtype expressing TIE2, a tyrosine kinase receptor. The TIE2 macrophages are involved in angiogenesis (Fagiani and Christofori, 2013). These TIE2 macrophages recruited by CCL3, CCL5, CCL8, and TIE2-ligand Ang 2 are considered the most important reason for tumor vascularization because the deficiency of this cell type restricts the angiogenic switch (Ngambenjawong et al., 2017).
TAMs are plastic. The simple dichotomy of M1/M2 macrophages cannot account for the complexity of TAM heterogeneity (Ostuni et al., 2015). Transcriptome analysis uncovered a spectrum model of TAMs (Xue et al., 2014). M1 and M2 macrophages can be regarded as two ends of a continuum with wide ranges of functional states (Mantovani et al., 2002; Ostuni et al., 2015); the sub-populations of TAMs in between the two ends can share features of both M1 and M2 types (Qian and Pollard, 2010). For example, recently Singhal et al. (2019) found that TAMs could co-express M1/M2 markers, together with T cell co-inhibitory and co-stimulatory receptors.
The dynamic nature of the TME cellular environment gives a basis for the plasticity of TAMs. Macrophages present reversible changes in their functional phenotypes and distribution in response to different microenvironmental stimuli, including various cytokines and locally derived molecules, which are tissue- and tumor-specific (Stout et al., 2005; Okabe and Medzhitov, 2014; Ostuni et al., 2015; Kim and Bae, 2016). Therefore, in different histotypes of tumors (Zhang et al., 2014; Cassetta et al., 2019) and different microregions of the same tumor (Mantovani et al., 2002; Kim and Bae, 2016; Yang M. et al., 2018), there can be TAMs with different extent of infiltration and functional status.
In ovarian cancer, Zhang et al. (2014) found the density and the cancer islet/stroma ratio of TAMs vary among serous, mucinous, endometrioid, clear cell and undifferentiated histotypes. In the stroma and lumina of a small number of patient ovarian tumor samples, limited frequencies of iNOS expressing TAMs were found, which were thought to be cytotoxic (Klimp et al., 2001); in contrast, in the malignant ascites of ovarian cancer, abundant TAMs can be found, which are primarily M2-like with pro-tumor capacity (Gupta et al., 2018). As the tumor grows, stimuli in the TME alter, resulting in changes in TAM infiltration and polarization in a tumor progression level-dependent manner. In ovarian cancer studies, TAM and M2 macrophage density were found to increase as cancer stage and ascites volume increased or as lymphatic invasion appeared (Zhang et al., 2014; Ke et al., 2016; Yuan et al., 2017; Gupta et al., 2018); contrarily, M1/M2 ratio decreased as cancer stage increased (Zhang et al., 2014).
Despite expressing similar markers, TAMs may not always have similar functional implications. In colon cancer study, TAMs expressing PD-1 presented weakened phagocytic potency, associating with reduced survival (Gordon et al., 2017), while in early lung cancer study the PD-1+ TAMs did not affect tumor-specific T cell attack against tumor (Singhal et al., 2019). This indicates the necessity of future studies focusing on TAM functional status in the context of tumor tissue types and stages of the disease; this is especially true with ovarian cancer as it has many histotypes and high heterogeneity.
Several studies revealed the prognostic value of TAMs in ovarian cancer. The M1/M2 and M2/TAM ratio have been reported to be positively associated with PFS and OS, while the overall TAM density in ovarian tumors indicated no prognostic significance (Lan et al., 2013; Zhang et al., 2014; Yuan et al., 2017). M2 density in the ascites or tumor samples is associated with reduced relapse-free survival (Reinartz et al., 2014) and PFS (Lan et al., 2013; Yuan et al., 2017). However, there is a controversy in the relationship between M2 density alone and OS: Lan et al. (2013) reported a negative association between the two factors, while Zhang et al. (2014) found no significant relevance. This may be due to the difference of included tumor histotypes.

Myeloid-derived suppressor cells (MDSCs)

Metabolické dráhy

  • Angiopoietin:
    •  this pathway can promote the growth of blood vessels in tumors
  • DLL/Notch:
    •  a pathway that can promote cell growth
  • Folate receptor alpha (FOLRa):
    • A protein commonly overexpressed in ovarian cancer
  • HER2: 
    • A pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • Mesothelin:
    •  a protein that is commonly overexpressed in cancer and may aid metastasis
  • MUC16/CA-125:
    •  a protein commonly overexpressed in ovarian cancer
  • RANKL: 
    • A protein that plays a role in bone regeneration and modeling, and is often overexpressed in cancer
  • TROP2:
    • A protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R:
    •  a pathway that can promote blood vessel formation in tumors

Metastázy

  • Cca 75% diagnosed at late stage
  • With widely metastatic lesions beyond the ovaries
  • Ovarian cancer predominately disseminates within the peritoneal cavity
  • Closely associated with ascites formation
  • Peritoneal carcinomatosis as well as ascites production associated with
    • Poor prognosis
    • Deterioration of the quality of life of the patients
  • Peritoneal metastasis of ovarian cancer
    • Shedding of cells from the primary tumor
    • Dissemination into the abdominal cavity
    • Attachment
    • Invasion into the mesothelial lining of the peritoneum
    • Formation of metastatic outgrowth
  • Disseminated tumor cells may aggregate into multicellular spheroids (MCSs) in ascites
    • With several advantages for further metastasis and chemotherapy resistance
    • Suspended MCS cells live much longer than the floating single cells that undergo anoikis
      • Important intermediate survival mechanism
        • Can facilitate ovarian cancer dissemination
  • Unvascularized spheroid
    • Generates a metabolite density gradient
      • Inhibits access of chemotherapy agents to the internal cells
  • MCS enters slowly cycling and/or quiescent states
    • Resistant to therapies that specifically kill proliferating cells
      • Such as taxanes
  • It is necessary to eradicate MCS completely in peritoneal cavity
    • To prevent tumor recurrence and metastasis
  • Formation of MCS
    • Leads to development of taxane resistance in ovarian peritoneum metastasis

Targeting inhibition of the molecules necessary for MCS formation

  • P27
  • P-glycoprotein
    • Reversed this resistance

Platinum

  • Most effective first-line reagent against ovarian cancer
    • As well as the most frequently used reagent for intraperitoneal chemotherapy
  • Resistance to platinum, whether primary or secondary
    • Relates to a poor prognosis

E-cadherin

N-acetylcysteine + paclitaxel

In ovarian cancer cells


Mutation of p53

Platinum-resistant disease (platinum-free interval of less than 6 months)

Relaxin peptide

  • Relaxin plays a central role in reproduction
  • Mediates
    • Follicle growth,
    • Endometrial differentiation
    • Uterine angiogenesis prior to implantation
  • Ovaries and prostate are the 2 major sources of relaxin in humans
  • Relaxin-2 (RLN2) and the highly similar RLN1
    • Coexpressed at low levels in multiple tissues
      • Decidua, placenta, endometrium, prostate, and myocardium
    • Autocrine and paracrine hormones
  • Relaxin peptides are processed from a propeptide form (pro-RLN)
    • To produce mature peptides containing an
      • A-chain linked
      • B-chain by 2 disulphide bonds
  • Activation, RXFP1 couples to the small G proteins G?s and G?i3
    • Initiate production of cAMP
    • Activation of PI3K
    • RAF/MEK/ERK (MAPK) signaling pathways
  • Relaxin may play a central role in multiple cancers
    • Cancers of reproductive origin
  • Pleiotropic hormone with reproductive functions in the ovary
  • Relaxin induces cell growth in several types of cancer
  • Relaxin and its associated GPCR RXFP1 form an autocrine signaling loop
    • Essential for OC in vivo tumorigenesis, cell proliferation, and viability
  • Relaxin signaling activates expression of prooncogenic pathways
    • RHO, MAPK, Wnt, and Notch
  • Relaxin is detectable in patient-derived OC tumors, ascites, and serum
  • Inflammatory cytokines IL-6 and TNF-alpha activated transcription of relaxin
    • Via recruitment of STAT3 and NF-kappaB to the proximal promoter
      • Initiating an autocrine feedback loop that potentiated expression
  • Relaxin/RXFP1 autocrine loop as a therapeutic vulnerability in OC
  • Relaxin expression is induced by inflammatory cytokines in OC-derived ascites
  • Relaxin levels were significantly higher in blood serum from the 48 OC patients
    • Relative to that from 14 normal controls (P = 0.01)
  • Relaxin can stimulate macrophages to produce IL-6
    • Relaxin signaling in tumor cells could be initiated
      • Sustained in the tumor microenvironment
  • Relaxin-stimulated OVCAR8 increased expression of IL-6 mRNA
    • In a dose-dependent manner
  • no effect on TNF mRNA was observed
  • Relaxin/IL-6 constituted a feedback loop
  • TNF-alpha treatment also increased relaxin expression in OVCAR8
    • Elevated RLN1 mRNA was observed in OVCAR8 following IL-6 or TNF-? treatment
  • Inflammatory cytokines may promote OC tumor progression through the induction of RLN expression.
  • Relaxin activates proliferative signaling pathways via RXFP1
  • Recombinant human relaxin (rhRLN2)
    • Induced increased viability in OVCAR8 and SKOV3
    • Increased BrdU incorporation
    • Activated MAPK and AKT signaling in OVCAR8
    • Promoted 5-fold increased cAMP production in OVCAR8
  • Relaxin autocrine signaling promotes survival in OC cells.

Ovarian CSCs

  • Population of cells that are often enriched in residual tumors following initial treatments with conventional chemotherapy
  • CSCs are directly associated with acquired chemoresistance in ovarian cancer
  • Assess CSCs as prognostic markers
  • Targeted therapies against CSCs have the potential to reduce tumor growth and improve patient prognosis
  • Combination of chemotherapy and CSC-targeted therapy
    • May be one of the most promising anticancer treatments for ovarian cancer
  • cdrjournal.com/article/view/3829

Cancer stem cells (CSCs) - "stemness of the tumor"

  • Suggested to play an essential role in cancer recurrence after initial chemotherapy.
  • CSCs may also be involved in chemotherapy susceptibility
    • Resistance to therapeutic agents
  • Association between CSCs and disease progression
  • Correlation of CSCs with poor prognosis
  • Enrichment of CSCs in tumor tissues following repeated chemotherapy cycles
  • Activation of major signaling pathways following chemotherapy
  • Combination of traditional chemotherapy and CSC-targeted therapy
    • Could be an effective and promising anticancer treatment for ovarian cancer
  • cdrjournal.com/article/view/3829

Treg cell infiltration

  • Indicated poor clinical outcomes
  • Curiel’s study - 104 women with ovarian carcinoma
    • Patients with advanced disease stage had a higher percentage of CD4+CD25+FOXP3+ Treg cells
  • Treg cells in the tumor sites
    • Were linked with decreased survival and a high death hazard (Curiel et al., 2004).

Regulatory T cells (Tregs)

Vitamin B6

  • Turkey, tuna, spinach, banana, lentils, and potatoes.
  • Typical doses range between 10 mg and 200 mg per day
  • Using more than 100 mg per day for more than two months
    • Chronic overdose may lead to sensory neuropathy.

A randomized clinical trial included 248 patients with stage III to IV ovarian epithelial cancer

  • 114 patients had prior chemotherapy and 134 did not randomized to
    • Cisplatin two doses of 37.5 mg per m2 or 75 mg per m2
    • + hexamethylmelamine 200 mg per m2 orally on days 8 to 21 of each 21 day cycle
  • Some + vitamin B6 at a dose of 300 mg per m2 orally on days 1 to 21
    • Cca equivalent to 7.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg
  • Overall response rate was 54%
  • 25% achieved a complete response
  • Patients receiving the higher dose of cisplatin
    • Had a greater response rate of 61%
  • Patients receiving lower doses had a response rate of 47%
  • Median response duration was 8.3 months.
  • Response duration was shortened in the vitamin B6 group of patients
    • Thus had an unfavorable effect on treatment effectiveness
  • Patients treated with higher dose cisplatin had more nausea and vomiting as well as increased neurotoxicity
  • pinestreetfoundation.org/ovarian-cancer-chemotherapy-antioxidants/
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Poslední aktualizace: 10. 12. 2023 21:48:21