Oncofertility: The Story of the Spermatogonial Stem Cell
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1 Oncofertility: The Story of the Spermatogonial Stem Cell James M. Hotaling, MD MS FECSM Co-director Fertility Integrated Practice Unit Asst. Prof of Surgery(Urology) Adjunct Asst. Prof OBGYN University of Utah Disclosures: Nanonc, StreamDx, Andro360 1R01HD , 1R01HD78641, HHMI (PI: Brad Cairns)
2 Sperm Cryopreservation Patients are now commonly requesting sperm extractions from terminally ill cancer patients 16 yo with lymphoma, intubated in ICU This is not the ideal time to think about banking
3 Overview Cancer treatment and reproduction Focus on chemotherapy NOT XRT, surgery Spermatogonial stem cells, population health and the future
4 Background 20,000 reproductive age men treated annually Focus on Quality of Life after treatment ASCO Guidelines: Offer Sperm Banking! No such thing as non-toxic chemotherapy, many infertile after treatment (24% azoospermic) Osterberg et al. Urology Annals 2014, Geneseca et al Cancer Genet cytogenet 1990, Lee et al. JCO Jahnukainen et al. Best Prac Clin metab 2011, Agarwal et al. Fert Ster 2004, Lopez Ped Hem ONC 2004,
5 Sperm Banking Can bank only 1 sperm and use for ICSI Lose 50-60% sperm with freeze-thaw, can freeze indefinitely Need >5M motile sperm post thaw for IUI OncoTESE cryopreservation IVF Nangia et al. Fert Ster 2013, Hone et al. Hum Reprod 2004,
6 Pretreatment Semen Quality Cancer Type Oligozoospermia (%) Testicular 28 Hodgkin s lymphoma 25 Leukemia 57 Gastrointestinal 33 Chung, et al. Eur J Obstet Gynecol Reprod Biol. 2004; 113: S7-11.
7 Improving Cryopreservation
8 Onco-TESE Testicular sperm extraction in an azoospermic men with cancer Approximately 50% recovery rate Prepubertal boys prior to treatment Cryopreservation of immature testicular tissue Future use for stem cell spermatogonia? Schrader M, et al. Urology. 2003;61: , Keros V, et al. Hum Reprod. 2007; 22: , Aslam I, et al. Hum Reprod. 2000;15: , Furuhasi et al. Andrologia 2013,
9
10 Congenital Anomalies in Offspring 2-3% incidence of congenital anomalies in general population Similar rates in offspring of cancer survivors No risk of de novo cancer in progeny Healthy offspring can be expected Li et al. JCI, Byrne et al. Am J Hum Genet, Boice et al. Health Phys, Green et al. JCO, 2009.
11 Cohort Subfertile 39,480 Relatives of Subfertile Individuals 274,190 Historical Subfertile Individuals (married, with complete fertility information born between , verified nulliparity) 10,614 Children of IVF/ICSI/IUI 14,372 N UDOH: Utah Department of Health - Vital Records (Birth, Death, Fetal Death) and Medical (Inpatient Discharge and Ambulatory Surgery) UUHSC: University of Utah Health Sciences Center IH: Intermountain Healthcare Fertile Controls (age and SES matched) Biobank specimens (linked to UPDB) 50,000 7,000 Key Data Sources Comprising the Utah Population Database UCR: SEER Utah Cancer Registry CDRI: Cancer Data Registry of Idaho (>700 azoospermic, banking GSU: Genealogical testicular tissue specimens Society monthly of Utah and >50 sperm samples monthly) DLD: Driver s License Division
12 Cancer in relatives of infertile men 13k men with semen analysis and fertile controls with 80k siblings, 435k cousins. Oligozoospermia 2x increased risk of any childhood cancer in sibs NOT cousins Are people predisposed to cancer predisposed to infertility? Anderson et al, J. Urol, accepted 12
13 Are the sperm relevant? Fertility? Embryogenesis Quality? Risk to offspring?
14 Lamarckian Evolution & Chemo Mice taught to fear an odor, both their offspring and the next generation are born fearing it. Gene for an olfactory receptor activated by the odor demethylated in the germ line Dias Nat Neurosci
15 Kubato & Brinster 2006 Germline stem cell therapy
16 Pluripotency versus Unipotency pluripotent Pluripotency Heterogeneous Unipotency (normally, only make sperm) Latent' Pluripotency (evidence: germ cell tumors, GPSCs) Profile RNA, DNAme, nucleosomes (+chemical marking/mod)
17 Loss of germ cell identity after culture Zheng et al., 2014
18 Mouse vs. human SSC development Adult Thy1+ Kit+ SSEA4+ Kit+ Shinaohara, 2013; Valli et al., 2014
19 Novel Signaling Pathways in Human SSCs Guo, Carrell, Hotaling & Cairns, submitted to Cell
20 SSC Goals 1. Understand Identity, Pluripotency, and Differentiation of Human Spermatogonial Stem Cell (SSC) (measure gene expression, signaling, and chromatin) 2. Define human SSC culture, and use molecular and genetic tools to further Goals #1 and #3. 3. Understand how germ cell tumors form, and how infertility might be treated? Dmrt1 Kit Kras Cdc27
21 Conclusions Cancer diagnosis sperm banking offered There is no fertility friendly chemo Impact of chemo is likely transgenerational Future of the field lies in culturing spermatogonial stem cells
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