Adipose tissue and related gynecological cancers George Valsamakis

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1 Adipose tissue and related gynecological cancers George Valsamakis Εndocrinologist Visiting Associate clinical Professor Warwick Medical School, UK European Scope Fellow in Obesity (IASO)

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3 Obesity and adipocyte changes Obesity is characterized by: 1. an increase in adipocyte size and number, 2. changes in the levels of adipocytokine secretion, 3. recruitment of macrophages that release proinflammatory cytokines.

4 Cytokines production sources Adipocytes (mature fat cells) Fibroblats (stromal cells, preadipocytes) Macrophages (infiltrate adipose tissue)

5 Adipose tissue cells in Obesity

6 Adipocytokine mode of actions Endocrine Paracrine Autocrine

7 Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression By L Vona Davis & DPRose Endocrine Related Cancer 2007

8 Η Δράση των λιποκυττοκινών

9 Λιπώδης ιστός και γυναικείο αναπαραγωγικό σύστημα

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11 Summary of Mortality from Cancer According to Body-Mass Index for U.S. Women in the Cancer Prevention Study II, 1982 through Calle EE et al. N Engl J Med 2003;348:

12 Tumour development Effects of metabolic surgery and cancer

13 Obesity and mortality from cancer (Calle EE et al. NEJM 2003) Prospective study of 900,000 adults (495,477 women) free of cancer at the enrollment period. 57,145 deaths from cancer during the 16 yr follow up. For men the relative risk of death was 1.52 and for women 1.62( ). In women significant trends of increasing risk with higher BMI values were observed for death from cancer of the breast, uterus, cervix and ovary

14 Type of Cancer breast No of deaths Death rate RR (95%CI) BMI BMI BMI BMI BMI> ( ) 1.63 ( ) 1.7 ( ) 2.12 ( ) P for trend <0.001

15 Type of Cancer BMI BMI BMI BMI>40 Corpus and uterus No of deaths Death rate RR (95%CI) ( ) 2.53 ( ) 6.25 ( )

16 Type of Cancer BMI BMI BMI BMI>40 P for trend cervical No of deaths Death rate RR (95%CI) ( ) 1.23 ( ) 3.20 ( ) 0.001

17 Diabetes and lipids: association with breast cancer Attner B Cancer Causes Control, 2012 how the incidence of cancer is related to diabetes, obesity or abnormal blood lipids. Diagnosis of diabetes, obesity or abnormal blood lipids was studied 0-10 years prior to the diagnosis of cancer in 19,756 cases of cancer and in 147,324 controls matched regarding age, sex. Diabetes was significantly more common prior to cancer diagnosis in patients with liver, pancreatic, colon and urinary tract/bladder cancer Diabetes more common in breast cancer patients diagnosed with diabetes 0-4 years prior to the cancer diagnosis.

18 Diabetes and lipids: association with breast cancer (2) Attner B Cancer Causes Control, 2012 Obesity was significantly more common in patients with endometrial, colon and kidney cancer and with breast cancer above the age of 60 years in those where obesity was diagnosed close to the diagnosis of cancer. High blood lipids were significantly more common in patients with ovarian cancer and less common in patients with breast cancer

19 Obesity and estrogen related cancer Premenopause: estrogens act in an endocrine manner maintaining tumor growth in ER-positive breast cancers Postmenopause: aromatization of Δ4 in adipose tissue is the source of estrone and estradiol

20 Paracrine action and cancer adipose tissue fibroblasts surrounding the cancerous lesion 1.aromatase activity enhancing local estrogen synthesis 2.steroid diffuses from its origin site to interact to ER in the nearby tumor cells

21 R Kaacs et al. (Endocrine Related Cancer 2010) Relative risk of breast cancer among postmenopausal women by quintiles of serum steroid concentrations

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23 Leptin-mechanisms Product of the ob gene Synthesized by adipocytes and preadipocytes Correlates positively with BMI Leptin levels higher in late follicular and luteal phase of the normal cycle Responsible for regulation of energy balance through effects at hypothalamus Conflicting results regarding serum levels and breast cancer risk (3 positive case-control studies vs 6 negative)

24 Paracrine actions Leptin on normal placental function during wound healing: produced by sc adipocytes for angiogenesis during repair process Local production in the anterior pituitary where it modulates thyrotropin secretion Paracrine activity in breast cancer cells when produced by surrounding breast fat cells

25 Autocrine action of leptin in breast cancer Presence of Leptin mrna and its corresponding protein in both ER positive and ER negative human breast cancer cell lines (O Brien et al 1999) Leptin receptors detected in the malignant epithelial cells of 83% of 76 invasive ductal breast carcinomas Activity at the tumor site to enhance the metastatic capacity of breast cancer cells (Ishikawa 2004, Garofalo 2006)

26 Leptin and cancerogenesis potential mechanisms Mitogen for various cell types (myelocytic, breast epithelial cells, vascular endothelial cells) Expression of leptin was found in normal mammary tissue, breast cancer tissue as well as in breast cancer cell lines Leptin-induced proliferation of breast cancer cell lines, increase of the expression of proteolytic enzymes that are essential in metastatic process stimulatory effect on angiogenesis Enhances aromatase activity. growth effect on estrogen receptor-positive human breast cancer cell lines through activation of MAP kinase protein pathway, of STAT 1,2,3 factors

27 Leptin and cancerogenesis: the evidence Activates ER in MCF-7 breast cancer cells without the involvement of estradiol (Catalano et al 2004) Interferes with the antiestrogenic action of pharmacological agents and stops the suppression of tumor proliferation (Garofalo 2004)

28 Επίπεδα λεπτίνης πλάσματος και καρκίνος μαστού: οι μελέτες

29 Breast Cancer Studies with leptin Mantzoros et al. (1999) found no difference between premenopausal patients with carcinoma in situ and healthy controls. An Italian case control study observed elevated plasma leptin levels in breast cancer patients and increase in adipose tissue leptin mrna levels (Tessitore et al. 2000, 2004). A study of invasive breast cancer from Greece reported significantly lower serum leptin levels in premenopausal breast cancer patients (Petridou et al. 2000).

30 Breast Cancer Studies with leptin (2) Miyoshi et al. (2006) no association between serum leptin levels and breast cancer risk correlation between serum leptin levels and intratumoral leptin mrna.(case control study)

31 Breast Cancer Studies with leptin (3) Chen et al. 100 controls & 100 newly diagnosed pre and post menopausal breast cancer patients serum leptin levels were not correlated to menopausal status signifnicantly higher in breast cancer group even at the absence of obesity

32 Εκφραση λεπτίνης και του υποδοχέα της στον καρκίνο του μαστού-αυτοκρινής δράση (οι μελέτες)

33 Leptin expression in breast cancer Enhanced Expression of Leptin and Leptin Receptor (OB-R) in Human Breast Cancer M Ishikawa et al. (Clinical Cancer Research 2004) 1. Leptin may have a promoting effect on the carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. 2. the expression of leptin and OB-R in breast cancer was significantly correlated (P < 0.01).

34 Leptin expression in breast cancer (2) Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity- Related Stimuli C Garofalo et al. (Clinical Cancer Research 2006) 1. Leptin and ObR were significantly over-expressed in primary and metastatic breast cancer relative to non cancer tissues. 2. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. 3. Conclusion Leptin and ObR are ove-rexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF- I, and/or estradiol

35 Insulin and IGF-1 in breast cancer Insulin directly stimulates proliferation of breast cancer cell lines and lowers the levels of SHBG thus increasing the free estradiol availability. Some authors also found relationship between elevated IGF-1 levels and the risk of breast cancer development in premenopausal women.

36 Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor by N.K. Saxena et al. Cancer Research 2008 Co-treatment with leptin and IGF-I increases proliferation as well as migration and invasion of breast cancer cells.

37 Adiponectin action (1) Negative relation with BMI, synthesized by mature adipocytes Present in serum as trimer, hexamer and high molecular weight isoform Protects from insulin resistance, inflammation and modulates endothelial function 2 receptors: AdipoR1 in skeletal muscle and adipose tissue and AdipoR2 in liver. Through AdipoR1 exerts effects by autocrine and paracrine mechanism (Rasmussen 2006, Kang 2005)

38 Adiponectin effects in breast cancer biology Increased breast cancer risk with hypoadiponectinaemia Antimitogenic effect in breast cancer cell growth Enhances tumor cell apoptosis Inhibits tumor angiogenesis

39 Adiponectin actions (2) Inverse association of plasma levels and breast cancer risk (Miyoshi 2003, Mantzoros 2004, Chen 2006) Suppressive effects on breast cancer cell growth in vitro The presence of receptors for the ligand protein both endocrine and paracrine mode actions at the cell level.

40 Adiponectin actions (3) Low levels are considered a marker of aggressive phenotype No relationship with ER status or to tumor grade or stage

41 Low Adiponectin levels and breast cancer risk Mantzoros et al. (2004) found 1. an inverse relationship of circulating adiponectin levels and breast cancer risk in postmenopausal women independently of possible effects of IGF-1, leptin, BMI and other parameters. 2. No such association was found in premenopausal women.

42 Low Adiponectin levels and breast cancer risk (2) Miyoshi et al. (2003) described 1. an association of low serum adiponectin levels with increased risk of breast cancer 2. in both postmenopausal and premenopausal women

43 Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer Shelley S. Tworoger JCEM 2007 Low risk for premenopausal women. Among postmenopausal women, adiponectin appeared more strongly inversely associated in women who never used PMH and women with low circulating estradiol levels Conclusion: Our results suggest that adiponectin may be inversely associated with postmenopausal breast cancer risk, particularly in a low-estrogen environment.

44 Απώλεια βάρους και καρκίνος μαστού

45 Figure. Relative Risk of Postmenopausal Breast Cancer Among Women Who Have Never Used Postmenopausal Hormones According to Weight Change Since Menopause. Eliassen, A. H. et al. JAMA 2006 Copyright restrictions may apply.

46 Unadjusted Cumulative Mortality. Sjöström L et al. N Engl J Med 2007.

47 Καρκίνος Ενδομητρίου

48 Obesity and endometrial cancer epidemiology (Bergstrom A.et al. Int. J. Cancer, 91: , 2001,) (Tornberg S. A. et al. Br. J. Cancer, 69: , 1994) Endometrial cancer incidence of 24 in 100,000 Accounts ~40% of endometrial cancer in affluent states more common in menopausal women Women who are obese are two to four times more likely to develop endometrial cancer in both pre and post menopause Οbese women who experience early menopause seem to be at an even greater risk.

49 How Obesity Increases endometrial Cancer Risk 1. Unknown mechanism 2. how much cancer risk increases with rising BMI can vary across ethnicities: ie:, Japanese-American women increase their endometrial cancer risk with only a small BMI increase, Caucasian and African-American women who increase their risk only with larger BMI increases.

50 Obesity endocrine effects-mechanisms Schmandt RE Am J Obstet Gynecol unopposed estrogen is a risk for hyperplasia and endometrial cancer. diabetes and hypertension are also often considered risk factors for this type of cancer, obesity seems to be the common link. Adipocytes express aromatase that converts ovarian androgens into estrogens, which induce endometrial proliferation. Lower Sex hormone-binding globulin levels, the level of unbound biologically active hormone is higher. The level of insulin-binding globulins is reduced and free insulin levels are elevated. Insulin and insulin-like growth factors (IGF) also exert a proliferative effect on the endometrium, through pathways that are already hyperactive in women at risk for endometrial cancer

51 Endogenous hormones and endometrial cancer development. Kaaks R et al. Cancer Epidemiol Biomarkers Prev 2002;11: by American Association for Cancer Research

52 Endometrial cancer and leptin (1) Petridou et al. (2002) a positive association between high leptin levels and endometrial cancer

53 Endometrial cancer and leptin (2) (Kitawaki et al.2000) short and long forms of leptin receptor mrna and proteins, but not leptin itself, were expressed in the endometrium The expression peaked -mainly the long form of leptin receptor -in early secretory phase and declined during the mid- and late secretory phases towards menstruation..

54 Endometrial cancer and leptin (3) Yuan et al. (2004) : 1. described elevated leptin levels in endometrial cancer patients. 2. The elevated leptin levels in endometrial carcinogenesis may reflect rather the obesity itself than the direct role of leptin in endometrial cancer development. 3. Lower expression of short leptin receptor isoform was observed in most endometrial cancers, especially in the poorly differentiated ones

55 Adiponectin and endometrial Petridou et al. (2003) cancer 1. showed an inverse significant association of endometrial cancer in women younger than 65 years of age. 2. Obesity and adiponectin had independent roles in promoting endometrial cancer. The results were confirmed in another study published by Dal Maso et al. (2004).

56 Adipocytokines and endometrial cancer Dallal CL et al. Endocrin Relat Cancer case-control study, (n=15,595), pre-diagnostic serum leptin, total adiponectin, and high-molecularweight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline ( ), and trial participation status.

57 Adipocytokines and endometrial cancer (2) Dallal CL et al. Endocrin Relat Cancer 2013 Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (OR=2.96; 95% CI, ; P trend <0.01). After further adjustment for BMI, the estimates were attenuated and the positive trend was no longer statistically significant (OR=2.11; 95% CI, ; P trend=0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin-bmi axis might increase endometrial cancer risk through mechanisms other than estrogendriven proliferation

58 Association of Obesity with stage-grade of endometrial cancer Reeves KV Gynecol Oncol 2011 prospectively examined the effects of body mass index (BMI) and waist-tohip ratio (WHR) on incidence, stage, and grade of endometrial cancer. studied postmenopausal women enrolled in the Women's Health Initiative.. Follow up 7.8 years, 806 women were diagnosed with endometrial cancer. incidence was higher among Whites, stage and grade were similar between Whites and Blacks.

59 Association of Obesity with stage-grade of endometrial cancer Reeves KV Gynecol Oncol 2011 (2) Elevated BMI (HR 1.76, 95% confidence interval [CI] ) and WHR (HR 1.33, 95% CI ) increased endometrial cancer risk. No associations were observed between BMI or WHR and disease stage or grade.

60 Association of Obesity with stage-grade of endometrial cancer (2) Lino Silva LS et al. Clin Transl Oncol 2013 Investigated BMI relation to clinical-pathological characteristics in primary tumor and disease outcome in endometrial cancer. 147 women primarily treated for endometrial carcinoma High BMI was related to endometrioid histology and low/intermediate grade In survival analysis adjusting for age, histological subtype and grade, BMI showed no independent prognostic impact. High BMI was significantly associated with markers of non-aggressive disease

61 Association between obesity and mortality in endometrial cancer Arem H et al. International Journal of Obesity (2012) performed a medline search,12 studies met inclusion criteria. Four of the included studies reported a statistically or marginally significant association between obesity and higher all cause mortality among endometrial cancer survivors after multivariate adjustment. Of the five studies that examined progression-free survival and the two studies reporting on disease-specific mortality, none reported an association with obesity.

62 Weight loss and cancer risk reduction: metformin effect Schmandt RE et al. Am J Obstet Gynecol Weight loss by diet, exercise, or bariatric surgery are all associated with this protective effect. Treatment with metformin is associated with: 1. a reduction in insulin level 2. weight loss 3. activates pathways that inhibit cell proliferation. 4. reduces adipocyte aromatase activity 5. increases progesterone receptor expression.

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