Prognostické faktory

Apoptóza

Extrinsic pathway

• Death receptors (DRs)
• Death-induced signaling complex (DISC)
• Aktivace caspase-8
• Cleaves Bid into truncated Bid (tBid)
• Translocating from the cytosol to the mitochondria [65]

Intrinsic pathway

Loss of mitochondrial membrane potential (MMP, ??m)

• Release of cytochrome c
• Activates caspase-9
• Caspases that cleave different substrates
• Dismantling of the cell [65]

Endoplasmic reticulum stress

Autophagy

• Conserved cellular degradation pathway
• For long-lived proteins and organelles [65]
• Induction of autophagy might maintain cancer survival under metabolic stress
• Mediate resistance to anticancer therapies [65]
• Inhibition of autophagy
• Enhances cancer cell death [65]
• Potentiates various anticancer therapies
• High levels of autophagy [65]
• Can induce a form of cell death known as type II cell death = autophagic cell death [65]
• Several cellular signaling pathways play a role in regulating autophagy
• Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) [65]
• Inhibiting Akt and its downstream target mTOR
• Contribute to the initiation of autophagy
• Initial stages of autophagy cellular proteins, organelles, and the cytoplasm [65]
• Autophagosomes
• Microtubule-associated protein 1 light chain 3 (LC3)
• Conjugated to phosphatidylethanolamine to form LC3-II [65]
• Recruited to autophagosomal membranes [65]
• Mature by fusing with lysosomes to form the autolysosomes
• Sequestered proteins and organelles are digested by lysosomal hydrolases [65]
• Recycled to sustain cellular metabolism [65]
• P62 was identified as an LC3-interacting protein [65]
• LC3- II present in the inner membrane of the autophagosome is degraded together with other cellular constituents by lysosomal proteases
• P62 trapped by LC3 is transported selectively into the autophagosome [65]
• The p62 protein localizes to sites of autophagosome formation
• Can associate with both the LC3 and ubiquitinated proteins
• P62 is considered to act as a receptor for ubiquitinated proteins, which it sequesters into the autophagosome
• Impaired autophagy is accompanied by accumulation of p62 [65]

Reactive oxygen species (ROS) [65]

• Formed by the incomplete reduction of oxygen
• Superoxide anion (O2-) [65]
• hydrogen peroxide (H2O2)
• Hydroxyl radicals (HO•)
• Intracellular redox homeostasis is a key determinant of cell fate
• Excessive ROS production usually results in cytotoxic effects [65]
• Might lead to apoptotic cell death
• Moderate levels of ROS function as second messengers
• Regulate diverse cellular processes such as cell survival, proliferation, and metastasis [65]
• Accumulation of ROS can induce autophagy,
• Facilitates the clearance of excessive ROS to protect cells from oxidative damage [65]
• ROS-mediated KEAP1 inhibition
• Activation of Nuclear factor-erythroid 2-related factor 2 (Nrf2)
• Expression of its target genes
• P62, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinine 1 (NQO1) [65]
• P62 stimulates autophagy
• Nrf2-mediated antioxidant response during oxidative stress [65]

Prognostické faktory nádorů žaludku

• Tumor growth is determined by
• The balance between proliferation and the apoptisis of tu mor cells

Antigens associated with proliferation

• Ki-67
• High proliferative activity have a worse prognosis [31]
• Pcna [31]

Circulating tumor cells (CTC)

• Presence of CTC is a major predictor of outcome in patients with gastric and gastroesophageal malignancies [6]

Hoxd10

• Was highly expressed in gastric cancer
• Correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, Tumor-Node-Metastasis (TNM) stage, and prognosis [7]

HOXB7

• Knockdown in BGC-823 and SGC-7901 resulted in
• Decreased migration and invasion [95]
• Alteration of epithelial-mesenchymal transition (EMT) proteins [95]
• Influenced proliferation, apoptosis, and cell cycle [95]

Expression of the enhancer of zeste homolog 2 (EZH2)

• A histone methyltransferase
• Correlated with poor prognosis in human gastric cancer [28]

trimethylation of H3K9

• Is positively correlated with tumor stage, lymphovascular invasion, cancer recurrence [28]

High expression of Sirt7

• Predicts poor survival [28]
• Sirt7 knockdown reduces gastric cancer growth in vitro and in vivo
• Mechanically, Sirt7 prevents apoptosis of gastric cancer cells
• Epigenetically silencing miR-34a via deacetylating H3K18ac [28]

bcl-2

• The positivity of bcl-2 was higher in metaplasia and probably is involved in the progression of carcinogenesis [29]
• Bcl-2 expression was more frequent in the early than in the advanced stages of the disease [31]
• More frequently expressed in the intestinal compared with the diffuse type [31]
• Importance of Bcl-2 in gastric carcinogenesis, especially during its early stages [31]
• Bcl-2 with cell cycle progression [31]
• Initially been detected in human B-cell lymphoma cells [57]
• A member of a protein family which has important tasks in the apoptotic mechanisms [57]
• Bcl-2 inhibits apoptosis [57]
• Doesn’t increase cell proliferation
• Provides survival advantage to the rapidly proliferating cells due to DNA damages
• In most cancer types, it is less related to aggressive cancer progression
• In non-small cell lung cancer, breast cancer, ovarian cancer, soft tissue sarcoma and colon cancer
• Increased Bcl-2 expression was a good prognostic factor [57]
• In some cancer types
• Adverse prognostic factor [57]
• Prostate cancer
• Increased Bcl-2 expression
• Associated with resistance to hormonal treatment and recurrence [57]
• Breast cancer
• Associated with dismal prognosis [57]
• Bcl-2 protein blocks the accumulation of calcium ion in the nucleus in cells exposed to tumor necrosis factor or thapsigargin [61]
• Overexpression of Bcl-2 protein in MKN-28 and KATO-III cells can interfere with [61]
• An ethanol-induced calcium ion mobilization [61]
• Accumulation of calcium ion in the nucleus [61]

p53

• Was negative in metaplasia and positive in more than half of the gastric cancer
• Mostly in stage IV, suggesting a late event in gastric cancer [29]
• Increased expression of p53 protein was observed in the adenocarcinomas (43.1%) [31]
• Compared with the adjacent normal mucosa (2.4%) [31]
• Positive correlation was noted between p53 protein expression and
• Tumor size,
• Histological classification and
• protein Ki-67 immunoexpression [31]
• In adenocarcinomas, p53 is unable to correct dnadamage
• Thus blocking apoptosis
• Allowing the proliferation of cells with dnadamage [31]
• Ineffectiveness of p53 in controlling the proliferation of cells with dna damage [31]
• The tumor protein p53 (TP53) acts by stopping the cell cycle and starting induction of apoptosis. In more than 50% of malignancies mutated p53 has been shown [57]
• In DNA-damaged cells, p53 stops the cell cycle at the transition from the G1 to the S phase
• DNA-damaged cells cannot proliferate
• Are removed by aptotic processes [57]
• Mutated DNA-damaged cells which express p53 continue to proliferate. In normal cells, p53 is expressed at levels which cannot be easily detected by immunohistochemistry
• P53 is located on the short arm of chromosome 17, and mutated p53 is formed as a result of various point mutations and deletions.
• The mutant p53 can be highly expressed in tumor cells [57]

Bcl-x

• Immunoexpression in 88% of gastric adenocarcinomas [31]
• Bcl-xl was also found to slow the apoptotic effect of chemotherapy on tumor cells [31]
• Increased expression of Bcl-x
• Helps to inhibit apoptosis
• Triggering the uncontrolled proliferation of tumor cells [31]

Bak

• Increased expression of Bak
• Sensitizes tumor cells to low doses of 5-Fu and cisplatin [31]
• Enhances apoptosis by binding to Bcl-xl and inhibiting its anti-apoptotic effect
• Increased expression of Bak and Bad
• Was observed in the adjacent mucosa [31]
• Low expression of Bak and Bad
• Was found in the adenocarcinomas [31]

Bax

• Reduced expression
• Negative prognostic factor in patients with cancer of the
• Breast, ovary, colon, esophagus and pancreas [31]
• Loss of Bax expression
• In acute lymphoblastic leukemia in children
• Associated with resistance to chemotherapy
• Inappropriate activation of the caspase cascade [31]
• Bax overexpression
• Sensitizes cells to chemotherapeutic agent-induced apoptosis
• Enhancing release of cytochrome c from mitochondria
• Cytochrome c released into the cytosol forms a complex with another molecule, Apaf-1, and the unprocessed proform of caspase-9
• In the presence of dATP or ATP this complex activates the caspases
• Trigger a cascade by activating caspases-3, -6, and -7
• Several potential chemopreventive agents also exert their effect through bax and bak

• Overexpression of bax and bak
• Involved in apoptosis induced by aspirin and indomethacin
• Without altering bcl-2 and bcl-xL expression

mTOR

• The mammalian target of rapamycin
• Serine/threonine downstream mediator in phosphatidylinositol 3-kinase signaling pathway
• Could directly phosphorylate the translational regulator eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 and S6 kinase (p70S6K)13
• MTOR signaling pathway
• Regulate proliferation, growth, survival and mobility [53]
• Targets of the mTOR kinase, as well as the proteins regulating mTOR [53]
• Often been activated or mutated in many types of cancer [53]
• Overexpression of phospho-mTOR
• Independent prognostic factor of human gastric cancer
• Inhibiting the activation of mTOR axis signaling
• Attractive cancer therapeutic strategy [53]

Cyclophilin A (CypA)

• Candidate target protein in gastric carcinoma
• Elevated expression of CypA in GC tissues compared with normal gastric mucosa was observed [96]
• Especially in TNM stage-I and intestinal type of tumor [96]
• Overexpressed in most GC cell lines
• Endogenous expression of CypA correlated with cell growth phenotypes [96]
• Suppression of CypA reduced the proliferation of BGC-823 and SGC-7901 GC cell lines [96]
• Exogenous CypA promoted the proliferation of NCI-N87 GC cells in a concentration dependent manner [96]

Androgen receptor (AR) activation

• AR promotes gastric cancer cell migration and invasion [98]
• Via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9 [98]
• Important role in many kinds of cancers [98]
• AR expression was positively correlated with lymph node metastasis and late TNM stages [98]
• Activation of AKT [98]
• Upregulation of matrix metalloproteinase 9 (MMP9)
• AR overexpression
• Induced increases in GC cell migration, invasion and proliferation
• Attenuated by inhibition of AKT, AR and MMP9
• Upregulated MMP9 protein levels - counteracted by AR siRNA [98]

EGFR

• Was found highly expressed in cancer tissues
• Correlated with lymph node metastases
• Knockdown of EGFR
• Reduced [97]
• Cell proliferation [97]
• Invasion of GC [97]
• Expression of AKT, PCNA and MMP-9 [97]
• Induced [97]
• Cell apoptosis [97]
• Cycle arrest [97]
• Upregulation of EGFR expression is associated [97]
• Lymph node metastases of GC [97]
• Blockade of EGFR signaling suppresses [97]
• Growth [97]
• Invasion of GC cells through AKT pathway [97]
• EGFR may represent a potential therapeutic target for this aggressive malignancy [97]

Rezistence k chemoterapii

Mutations in the p53 gene

Overexpression of bcl-2 and/or bcl-xL

• 72% overexpress bcl-2
• Inhibition of apoptosis through bcl-2 protein [62]
• Specifically associated with promotion of intestinal-type gastric adenocarcinoma
• Bcl-2 overexpression
• Strongly blocks apoptosis by inhibiting
• Cytochrome c release from mitochondria
• Caspase-3 activation

Down-regulation or mutations of bax or bak [62]

• Bax frameshift mutations 33–40% of gastric cancers [62]
• High level microsatellite instability [62]
• Missense Bak gene mutations in 12.5% of gastric cancers [62]
• Sequence alterations without amino acid alteration in 4.2% of gastric cancers

MicroRNA (miRNA)

• Modulates the expression of a great number of genes
• including MDR
• +expression of miR-1284 was reduced in gastric cancer [93]
• With metastasis [93]
• In vincristine-resistant (VCR) GC SGC7901 cells (SGC-7901/VCR)
• Recombinant lentiviral vectors with miR-1284 led to the overexpression of miR-1284 mRNA [93]
• Reversed the chemoresistance of SGC7901/VCR cells
• Promoted cell cycle arrested at the G0/G1 phase [93]
• Accelerated drug-induced apoptosis
• Decreased migration and invasiveness of SGC-7901/VCR [93]
• Sensitized tumors to chemotherapy in vivo
• MiR-1284
• Can heighten the expression of MYC [93]
• Reduce the expression of JUN, MMP12, and EIF4A1
• Can function as a new regulator to reduce GC MDR cells by targeting EIF4A1 [93]

Markery

• Butanoic acid
• Butanoic acid 10.9 µmol / L or more [1]
• Hexanoic acids
• 15.9 µmol / L or less [1]

Literatura:

Immune-Cell Infiltration

• Significance of Immune-Cell Infiltration in Gastric]
• Tanaka H et al, Gan To Ganaka Ho Ryuhu 2018

• ”bylo prokázáno, že CD8+ T buňky reagují v u pokročilého karcinomu žaludku antigen-specifickým způsobem
• Možnost, že paměťové T-buňky, NK-buňky a NKT buňky v tkáních žaludečního karcinomu korelují s dobrou prognózou
• Přítomnost folikulárních lymfoidních struktur, nazývaných „terciární lymfoidní struktura“ (TLS), ve tkáních žaludečního karcinomu souvisí s lepší prognózu pacientů“...