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Endometriosis Part 4-Cancer Cytogenetic-Lecture Slides, Slides of Cancer Cytogenetics

This lecture was delivered by Prof. Akhilesh Kulkarni at Sree Chitra Thirunal Institute of Medical Sciences and Technology. This is part of Cancer Cytogenetic course. It includes: Mesothelium, Amniotic, Fragments, Endomaterial, Adhsion, Molecules, Metalloproteinases, Collagen, Matrix, Elastin

Typology: Slides

2011/2012

Uploaded on 08/01/2012

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Attachment to Mesothelium
Amniotic membrane vs peritoneum with respect
to expression of cytokeratins in epithelial lining
Endometrial fragments do not adhere to the
epithelial side of the amniotic membrane
Adhesion does occur on the non-epithelial side
Intact epithelial lining may prevent initial
adhesion of retrogradely shed endometrium
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Attachment to Mesothelium Amniotic membrane vs peritoneum with respect to expression of cytokeratins in epithelial liningEndometrial fragments do not adhere to theepithelial side of the amniotic membrane Adhesion does occur on the non-epithelial side Intact^ epithelial lining may prevent initialadhesion of retrogradely shed endometrium

Adhesion Molecules IntegrinsIntracellular adhesion molecule-1Vascular cell adhesion molecule-1Integrin-blocking antibodies do not interfere with endometrial stromal or epithelial cell adherence to mesothelium

Matrix Metalloproteinases^ collagen^ gelatins^ proteoglycans^ laminin^ fibronectin^ elastin

Matrix Metalloproteinases Increased

MMP

activity

in^ and

around

the

endometriotic

implants

may

facilitate

invasion

and growth of lesions. Progesterone down regulates endometrial MMPexpression

Transforming growth factor-

β^ (TGF-

TGF-

β^ alone does not lead to sustained

suppression of MMPsPossibly because of resumption of MMPproduction in the absence of progesterone Consistent with the fact that peritoneal fluidlevels of TGF-

β^ are elevated in endo

Interleukin-1 (IL-

Potent stimulator of MMP-3 in proliferative phase endometrium Progesterone exposure in vivo reduces the IL-

α^ stimulation of MMP-3 in

secretory phase tissueIL-1α^ stimulation of MMP-3 is restored in a dose-dependent manner with progesterone withdrawalCultured endometriotic cells obtained from a rat endo model express higher levels of MMP-3 mRNA than eutopic rat endometrial stromal cellswhen treated with progesteroneElevated and persistent MMP-3 expression by endometriotic stromal cells cultured in the presence of progesterone correlates with elevated levels of IL-1α^ mRNA detected in the endometriotic stromal cellsProduction of IL-

α^ by the endometriotic lesions - overcomes the progesterone-induced suppression of MMP-3 IL-1α^ - related mechanism promotes MMP-3 production by endometrioticcells even in the presence of progesterone

Pelvic Inflammation

Contributes to pain and infertilityCytokinesProstaglandins

DyspareuniaChronic pelvic pain

Inflammation --> Infertilityadhesion formationscarringdisrupt fallopian tube patencyimpair folliculogenesisfertilizationembryo implantation

Macrophages

Most abundant nucleated cells found in peritoneal fluidIncreased in the peritoneal fluid of women withendometriosis Promotes growth of ectopic endometrium (paradox ?) Increase in the release of growth promoting cytokines

Natural Killer Cells (NK)

Decrease in NK cell activity may lead to impaired clearance of regurgitated endometrial cells from the peritoneal cavityDecreased cytotoxic activity against autologous andheterologous endometrium More pronounced in the moderate and severe stages of endoSera and peritoneal fluid from women with endo suppressNK cell cytotoxicity Higher killer-inhibitory receptorsexpression Send inhibitory signals that override the kill signal andsuppress cytotoxic activity

Lymphocytes

T-cell mediated immunity to autologous endometrium is suppressedCytotoxic activity of peripheral blood lymphocytesagainst autologous decreased Functional alteration not accompanied by a quantitativedown regulation Total in the peripheral blood are not affected markedlyNo change in total lymphocyte content orhelper/suppressor ratios T-lymphocyte concentration is increased in theperitoneal fluid

Endometriomas and extra-ovarian endometriotic^ implants express high levels of aromatase

Cultured stromal cells derived from endometriotic implants andincubated with a CAMP analog display extraordinarily high levels ofaromatase Growth factors, cytokines - possible inducers of aromataseProstaglandin E

was identified as the most potent inducer 2 Estrogen - up-regulates prostaglandin E

formation 2

Stimulates cyclo-oxygenase type 2 enzyme in endometrial stromal cells Positive feedback loop for continuous local estrogen andprostaglandin E

production 2 Possible genetic defect in aromatase expression in endo

Possible role of Aromatase in Endometriosis

Androstenedione of adrenal and ovarian origins – premenopausalwomenAdrenal androstenedione in postmenopausal womenEstrone - weakly estrogenic Must be converted to estradiol 17 α-hydroxysteroid dehydrogenase (

α-HSD) type 1 is expressed

in endometriosis In contrast 17

α-HSD type 2 inactivates estradiol by catalyzing its conversion to estrone in eutopic endometrial glandular cells duringthe luteal phase Progesterone induces the activity of 17

α-HSD

Inactivation of estradiol to estrone one of the anti-estrogenicproperties of progesterone 17 α-HSD type 2 is absent from endometriotic glandular cells