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Studying the mechanisms of Cd-induced stem cell proliferation and their role in tumor avoidance in Schmidtea mediterranea

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Abstract

Flatworms are acknowledged for their stem cell system and consecutive regenerative ability. From a toxicological point of view, stem cells are an interesting object of study, as they enable organisms to cope with stress. Previous research on the freshwater flatworm and model organism Schmidtea mediterranea revealed a substantially higher general (systemic) coping capacity towards Cd in regenerating versus intact animals. Consequently, active regeneration seems to reinforce the defense system. In addition, this species was found to exhibit a remarkable resilience towards tumorigenesis. Administration of carcinogenic compounds like Cd, Cr(VI) and methyl methane sulphonate never resulted in any tumor-like outgrowths, but it did always induce a characteristic stem cell (proliferation) response. The aim of this research project concerned a detailed characterization of the underlying mechanisms during Cd-induced stem cell proliferation. This was initially done by investigating whether several well-studied cancer-related genes could act as key players in the tumor avoidance capacity of S. mediterranea. The results of this study demonstrated that tumor suppressor P53 has an essential role in stem cell survival and self-renewal, but remarkably not in tumor suppression itself. Subsequently, tumor avoidance was studied via an open screening at the proteome level. That analysis revealed an important role for matrix related proteins in modulating the extracellular environment and directing cell fate under stress. As such, the stem cell niche might play an essential role in the defense of regenerative tissues against tumorigenesis.
Studying the mechanisms of Cd-induced stem cell proliferation
and their role in tumor avoidance in Schmidtea mediterranea
Frank Van Belleghem1, Andromeda Van Roten2, Tom Artois2, Karen Smeets2
1Faculty of Management, Science and Technology, Department of Science, Open Universiteit, The Netherlands
2Centre for Environmental Sciences, Research Group Zoology: Biodiversity & Toxicology, Hasselt University,
Campus Diepenbeek, Belgium
Introduction:
Hypothesis:
Regeneration & carcinogenesis
Sheds new light on carcinogenesis
Plasticity of the stem cell system
=
defense mechanism to circumvent
carcinogenesis
Methods:
Regeneration vs cancer
Organismal &
Cellular effects
Mechanisms in cancer circumvention
Targeted Approach:
Cancer-and regeneration related
genes
Open Screen:
Mechanisms in
tumor avoidance
Time point
LC50
Adults
(μM CdCl2)95% C.I.
LC50
Regenerates
(μM CdCl2)95% C.I.
Day 2 95 86 112 99 87 -127
Day 3 84 76-92 96 89 112
Week 1 60 54 67 83 75 94
Week 2 40 35 45 59 55 64
Week 3 26 -37 32 41
Results (Organismal & Cellular effects):
Conclusion:
Regeneration vs cancer
Org. & Cell. effects: Cd induced stem cell response, no outgrowths
Mechanisms in cancer circumvention
Targeted Approach:
Tumor suppressor genes
not crucial in tumor
avoidance in reg. tissues
Open Screen:
Matrix related proteins
Tumor suppressor
function in regenerating
S. mediterranea
Role in tissue remodeling
Earlier mitotic stem cell response in regenerates
Increased LC50 in regenerates
Intact adults Regenerates
Results (Targeted Approach):
Results (Open Screen):
No outgrowths observed neither in intact adults nor in regenerates
Cd effect on Smed-p53 KD phenotype: earlier & aggravated
Smed-p53 Control 10 μM Cd KD KD + 10 μM Cd
Regenerating
trunk
Appearance of KD phenotype Day 15 Day 9
Histone H3 staining of mitotic
stem cells in S. mediterranea
KD MRP1 KD MRP2
Tumor-like outgrowths,
some reveal protrusion
discarding capacity
Tumor-like outgrowths
KD MRP2 (H&E)
Knockdown (KD) of 17 cancer-related genes no outgrowths
Proteomic screen of Cd-induced stem cell proliferation
Knockdown of matrix related proteins (MRP) outgrowths
Transcript levels of stem cell, progeny and stress-response markers in
smed-gfp (RNAi) and smed-p53 (RNAi) trunk regenerates exposed to 0μM and
10μM CdCl2for 11 days (overall effect: p<0,1; * p<0,05; ** p<0,01; ***
p<0,001). Post hoc analysis results in this table are indicated by different letters
(p<0,05)).
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