Colleagues - Alvin J. Siteman Cancer Center

Adrenocortical tumors in childhood
Previewing themes in the
Cancer Biology course
David Wilson
Pediatric Hematology-Oncology
The major steroidogenic organs derive from a
common pool of progenitors
Organization of the mammalian adrenal gland
Phenotypic plasticity of adrenal steroidogenic cells
• Cell proliferation
occurs in the
subcapsular region.
• Cells in different
zones have a common
origin; their phenotype
depends on
environmental cues.
Chimeric adrenal gland derived from injection of
GFP-tagged mouse ES cells into a blastocyst
Clinical case 1
• 2-year-old boy with irritability, weight gain, and acne.
• Endocrine evaluation reveals high serum cortisol and
DHEA-S in the setting of a low serum ACTH.
• CT scan demonstated a L
adrenal tumor, which was
completely resected.
• Pathology consistent with
adrenocortical adenoma.
• Patient is now a healthy teen.
Cushingoid features
due to excess glucocorticoids
Clinical case 2
• Previously healthy, athletic teenager.
• 3 mo of unexplained weight gain (particularly facial
and abdominal fat).
• New onset acne.
• High blood pressure.
• Endocrine evaluation reveals high serum cortisol and
low serum ACTH.
The left adrenal was resected;
histopathology showed a large adrenocortical carcinoma.
Adrenocortical neoplasms in humans
• Adenoma. 5% of people over the age of 50 have at
least one small, non-functioning benign tumor
(“incidentaloma”). Benign tumors that secrete
hormones are uncommon.
• Adrenocortical carcinoma (ACC). These malignant
tumors are rare (1 case/million per yr) but carry a
poor prognosis because of their propensity to spread
before detection. These are usually functional.
• The factors that account for the frequent occurrence
of adenomas and the low rate of ACC have been the
subject of intense investigation over the past decade.
Clinical case 3
• 3-year-old previously healthy female.
• 1-2 month history of hair loss.
• 10-15% weight loss.
• Changes in external genitalia suggestive of
inappropriate sex steroid production.
• Imaging reveals adrenal gland enlargement.
Disruption of the HPG axis leads to
sex steroidogenic tumor formation
Two markers of gonadal differentiation, GATA4
and LHR, are expressed in the neoplastic
adrenocortical cells of the ferret
“We thank Rosie Wilson for technical assistance.”
Hair loss reflects ectopic sex steroid
production by the ferret adrenal
Baldness is seasonal
Shift to long day photoperiod causes an
increase in plasma LH levels in ferrets
No OVX induced
increase in LH
Adrenocortical neoplasia in various species
GDX-induced adrenocortical neoplasia in mice
Ectopic expression of gonadal markers in the
neoplastic adrenocortical tissue
An overlooked
model of tissue
type switching
Genome wide linkage analysis of crosses
between DBA2/J and C57Bl/6 mice
• C57Bl/6 x DBA2/J F1 (B6D2F1) mice, like the parental
DBA2/J strain, develop post-GDX tumors with near
complete penetrance by 6 mo after surgery, suggesting
that tumor predisposition is a dominant trait.
Tumor Formation
Bernichtein, S. et al. Endocrinology 2008;149:651-661
Conclusions of the linkage analysis
• GDX-induced adrenocortical neoplasia is a complex
trait influenced by multiple genetic loci.
• Analysis revealed one major locus for tumorigenesis
on chromosome 8, modulated by epistasis with
another locus on chromosome 18.
• The genes responsible have not been identified.
• Adrenocortical neoplasms are common in humans;
range from adenomas to carcinomas.
• Functional adrenocortical neoplasms are very
common in certain gonadectomized animals, such as
goats, ferrets, hamsters, and mice.
• GDX-induced adrenocortical tumors express gonadal
markers (e.g., GATA4 & LHR) and may produce
ectopic sex steroids that cause significant morbidity.
Prevalence of adrenocortical neoplasms in children
case 1
case 2
Prevalence of adrenocortical neoplasms in humans
parallels that of brain tumors
David Gutmann
Josh Rubin
What genetic, developmental, and anatomic factors impact
tumorigenesis in children vs. adults?
Too much signaling can be a bad thing
Bob Heuckeroth
Dan Link
Role of signaling pathways in tumorigenesis
TP53 R337H mutation and childhood
adrenocortical tumors in Brazil
TP53 R337H mutation and childhood
adrenocortical tumors in Brazil
Germline and somatic mutations leading to cancer
Todd Druley
Paul Goodfellow
What genetic factors impact tumorigenesis
in children vs. adults?
A multipotential stem/progenitor cell is posited to give
rise to both corticoid- and sex steroid-producing cells
WNT/b-catenin signaling has been implicated in
adrenocortical stem cell maintenance & in tumorigenesis
WNT/b-catenin signaling and the regulation of stem cell
proliferation/differentiation using Drosophila models
Craig Micchelli
Epigenetic alterations at the IGF2 locus are common in
adrenocortical carcinoma
Epigenetic alterations at the IGF2 locus drive stem cell
proliferation and inhibit differentiation/apoptosis
Feinberg’s epigenetic progenitor model of cancer
• Epigenetic changes precede and heighten risk of cancer in
response to oncogenic mutations.
• Step 1 is an epigenetic disruption of progenitor cells within an
organ or tissue, altered by abnormal regulation of tumorprogenitor genes. This leads to a population of cells ready to
cause new growth.
• Step 2 involves an initiating mutation within the population of
epigenetically disrupted progenitor cells at the earliest stages of
new cell growth, such as the rearrangement of chromosomes in
the development of leukemia. This mutation normally has been
considered the first step in cancer development.
• Step 3 is genetic and epigenetic instability, which leads to
increased tumor evolution.
Evidence supporting two conceptual models of
adrenocortical neoplasia
Do clonal preexisting epigenetic changes impact the
ability of stem cells to respond to LH?
Studies of the emergence of metastatic cells
Bill Harbour
Studies of ocular melanoma using copy number variation analysis,
mRNA and miRNA profiling, and epigenetic profiling to study tumor
propagating cell populations within the primary tumor.
ACC is not readily cured by chemotherapy, so novel
treatments are needed
New therapies for the treatment of cancer
Nancy Bartlett
A multipotential stem/progenitor cell is posited to give
rise to both corticoid- and sex steroid-producing cells
Gata4 haploinsufficiency attenuates
GDX-induced adrenocortical neoplasia in B6D2F1 mice
Reduced adrenocortical tumor size in
Gata4 haploinsufficient mice
Relative expression of sex steroidogeneic
markers in WT vs. Gata4+/- adrenals

similar documents