embryonal growth factors, their receptors, signalling pathways and their laboratory/clinical benefits.

1. EMBRYONAL GROWTH FACTORS
OLAGBAYE, Babakayode Abel
Dept of Anatomy
University of Ilorin
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2. OUTLINE
OVERVIEW
• What are growth factors
• What do they do
GFs
SPECIFICITY
• Families of growth factors
• And their receptors
REGULATORY
ROLES Of GFs
• Regulation of Proliferation & Differentiation
• Regulation of cell migration and path finding
• Regulation of cell death and apoptosis
COMPLEXITY &
DYSFUNCTION
• The complex signalling pathways of GFs
• Implication of some GFs deficiency
GF s IN
EXPERIMENTAL
EMBRYOLOGY
• The use of GFs in Embryological researches
• Problems and Pitfalls in embryonal growth factor
researches7/12/2017 2

3. What are Growth Factors
They are regulatory molecules that reach cells by
an extracellular route, they promote and guide
virtually every step of embryogenesis i.e
proliferation, differentiation,
migration/pathfinding and survival/death
How Do They Work
They communicate with cells from the extracellular
space and influence intracellular events by
binding to specific Transmembrane Receptors
that in turn transduce such interactions by
activating intracellular signalling pathways.
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4. Growth factor families and their
receptors
• EGF - EPIDERMAL GROWTH FACTOR
• FGF - FIBROBLAST GROWTH FACTOR
• NGF - NERVE GROWTH FACTOR
• TGFβ - TRANSFORMING GROWTH FACTOR
BETA
• INSULIN & IGF’S (INSULIN-LIKE GROWTH
FACTORS)
• PDGF- PLATELET DERIVED GROWTH FACTOR
• Thomas et al., 2007
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5. GFs Family Cont’d
• HEDGEHOG PROTEINS
• WNT’S
• INTERLEUKINS
• SLIT’S
• NETRINS
• EPHRINS
• TUMOR NECROSIS α FAMILY (TNFα’S)
• Thomas et al., 2007
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6. GFs - Receptor Interactions
• Four basic modes
1. Long-range dispersion via the circulation (e.g., IGFs)
2. “Paracrine” mechanisms of release by local sources
(e.g., TGFβ, FGFs, EGFs),
3. “autocrine”: mechanisms in which a cell responds to
growth factors that it produces itself (e.g., WNTs)
4. “juxtacrine”: direct cell-cell interactions in which the
growth factor is itself presented as a transmembrane
protein (e.g., Ephrins, Notch, Hippo)
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7. GFs RECEPTORS
• There are cases in which more than one family
member binds to a single receptor and cases
in which a given family member binds to
multiple receptors.
• There are also just 4 FGF receptors for the 22
members of the FGF superfamily.
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8. 7/12/2017 8

9. • Using Neural Crest cell formation as a case study
GROWTH FACTOR as regulators of
cell migration/pathfinding
• WNT blocks Adipocytes proliferation and maturation
GROWTH FACTOR as negative
regulator of Differentiation
• As in the case of Insulin dependent growth factor
GROWTH FACTOR as overall growth
regulator
Growth Factors as positive and Negative
regulators
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10. 7/12/2017 10

11. In some cases, growth factors can also
block cell proliferation
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12. Epidermal growth factors (EGF, amphiregulin, neuregulin and
transforming growth factor-α)
• 15% of patients with non-small
cell lung cancer have
mutations to the EGFR. The
type of mutation to EGFR may
predict whether certain types
of drugs (tyrosine kinase
inhibitors TKIs), can help treat
lung cancer.
Produced in the
fibroblast cells of the
dermal layer, and it
works to stimulate
cells
to produce collagen
Skin cell proliferation; eyelid
development, teeth
eruptionoverall
development and growth.
(Ishiwata et al., 2000)
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13. Transforming growth factors (TGFs)
Includes TGF-β, activin
and bone
morphogenetic/
proteins (BMP).
• Dorsoventral
patterning, cell fate
decision and formation
of specific organs
including the nervous
system, kidney,
skeleton and blood
(Ishiwata et al., 2000).
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Activin enhances FSH biosynthesis and secretion, metabolism,
homeostasis, immune response, wound repair, and endocrine
function (Chen et al., 2006).

14. Fibroblast Growth Factors (FGFs)
FGF plays a minor role in homeostasis, inflammation and remodeling
and a major role in granulation tissue formation.
FGF-1 induce endothelial cell proliferation, and is chemotactic for
both endothelial cells and fibroblasts.
FGF-2 stimulates myeloid progenitors. They also stimulates stromal
growth directly or by inducing differentiation of a common stem cell
into stromal-type cells.
FGF-5 in the embryo is notable for its highly specific pattern of
expression.
FGF-6 appears to play a major role in skeletal muscle development.
FGF-7 expression is markedly increased in fibroblasts underlying the
epidermal layer. (Baird and Bohlen, 1990).
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15. (FGFs) Signaling pathway
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16. Iseki et al., 1999
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17. Insulin-like growth factors (IGFs)
• The insulin family comprises somatemedins A and C, insulin,
insulin like growth factor and multiplication-stimulating factor
(MSF).
• They are mitogenic stimulating the fetal metabolism and
coordinating the feto-placental metabolism.
• IGF-II regulates early embryonic development while IGF-I is
responsible for the general growth of the newborn.
(Butler and LeRoith, 2001).
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18. IGF signalling pathway
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19. 7/12/2017 19

20. PDGF signalling pathway
consists of
dimers of
either
A (17 kDa),
B (16 kDa) or
AB chains
linked via
disulphides
• PDGF is regarded as an initiating factor in the cell cycle
in that it stimulates the advance of quiescent cells
Platelet-derived growth factor
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21. Nerve Growth Factor (NGF)
Nerve growth
factor (NGF) is a
neurotrophin
released by
muscles that
promotes the
survival and growth
of axons, survival of
neurons, and in the
innervations of
target tissues.
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22. Other Embryonal Growth Factors
• Transforming growth factor alpha (TGFα): act to stimulate cell
growth as well as inhibit cell growth, depending upon the situation.
• Tumor Necrosis Factor (TNF): Inhibits growth of tumor and other
cells by initiating programmed cell death.
• Inhibin down regulates FSH synthesis and inhibits FSH secretion
(16-18 weeks).
(Chen
et al., 2006).
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23. 7/12/2017 23

24. Now let’s see some
Growth
factors in
Embryological
researches
Therapeutic
use of GFs and
their pitfalls
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25. Role of GFs in Cancer Progression by Witsch et al., 2009
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EGF and IGF1 support the consequent
expansion of mutation-bearing clones
clonal expansion
Invasion refers to the migration and
penetration by cancer cells into
neighboring tissues TGF, FGF, EGF
Cancer cells disseminate
lymphatic and blood vessels to
Angiogenesis by VEGF FGF establishes
secondary tumors larger than 1ml
Chemotherapy/Radiotherapy can
help acquire new mutations and the
ability of cancer cells to produce GFs
(TGFalpha, NRG) to propel the
outgrowth of resistant clones

26. Therapeutic
targeting of
growth
factor
signaling
pathway in
solid tumors
Maitland et al., 2010
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27. Tumor suppressing activity of TGFβ
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All immune cell lineages, including B-Cell, T-Cell and dendritic cells as well as
macrophages secrete TGF-Beta, which negatively regulates their proliferation,
differentiation and activation by other cytokines. Thus, TGF-Beta is a potent
immunosuppressor and perturbation of TGF-Beta signaling is linked to autoimmunity,
inflammation and cancer

28. Perrimon et al., 2012 examined signalling pathways that
determine cell fate and embryonic patterning
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29. Lateral cell inhibition of NOTCH DSL ligands
This mechanism is used
widely in research to
pattern tissues
containing initially
identical cells.
It is also used to select
myoblast founder cells
in the mesoderm
DYSFUNCTION OF NOTCH
Allagille and CADASIL
syndromes, as well as
cancer, where it promotes
tumor growth in some
contexts but can prevent it
in others
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30. Side effect of BMP-2 therapy by James
et al., 2016
• Bone morphogenetic protein-2 (BMP-2) is currently the only
Food and Drug Administration (FDA)-approved osteoinductive
growth factor used as a bone graft substitute
• SIDE EFFECTs
• Postoperative inflammation and associated adverse effects,
• Ectopic bone formation,
• osteoclast-mediated bone resorption,
• Inappropriate adipogenesis.
• Tumorigenesis (controversial).
• potential molecules to mitigate the adverse effects of BMP-2
are currently being reviewed.
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31. Pitfalls of using GFs in Embryological
researches (Kane et al., 1997)
• The ‘bandwagon’ problem
• Problems in the use of gene knockout to
study growth factor requirements
• The problem of the mouse embryo as a
model
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32. References• Butler AA, LeRoith D Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and
their roles in insulin-like growth factor physiology. Endocrinology. 2001 May ;142(5):1685-8.
• Tiedemann H, Asashima M, Grunz H, Knochel W. Dev Growth Differ. 2001 Pluripotent cells (stem cells) and their
determination and differentiation in early vertebrate embryogenesisOct ;43(5):469-502.
• Nakae J, Kido Y, Accili D . Endocr Rev. 2001 Distinct and Overlapping Functions of Insulin and IGF-I ReceptorsDec 1
;22(6):818-835.
• Sullivan LC, Orgeig S, Wood PG, Daniels CB .The ontogeny of pulmonary surfactant secretion in the embryonic
green sea turtle (Chelonia mydas).. Physiol Biochem Zool. 2001 Jul-Aug ;74(4):493-501.
• Ishiwata I, Tokieda Y, Kiguchi K, Sato K, Ishikawa H. Hum Cell. 2000 Effects of embryotrophic factors on the
embryogenesis and organogenesis of mouse embryos in vitroDec ;13(4):185-95
• Cui Y, Tian Q, Christian JL. Dev Biol. 1996 Synergistic effects of Vg1 and Wnt signals in the specification of dorsal
mesoderm and endoderm. Nov 25 ;180(1):22-34.
• Beau C, Vivian N, Munsterberg A, Dresser DW, Lovell-Badge R, Guerrier D. Mol Reprod Dev. 2001 In vivo analysis of
the regulation of the anti-Mullerian hormone, as a marker of Sertoli cell differentiation during testicular
development, reveals a multi-step processJul ;59(3):256-64.
• Baird, A. and P. Bohlen (1990) "Fibroblast Growth Factors" in Peptide Growth Factors and Their Receptors I, Sporn,
M.B. and A.B. Roberts, eds. Springer-Verlag, New York, p. 369.

33. For Listening
You
Thank
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