Biophysical and Biological Properties of Naturally Occurring High Molecular Weight Insulin-like Growth Factor II Variants

Valenzano, Kenneth J.; Heath-Monnig, E.; Tollefsen, Sherida E.; Lake, Mats; Lobel, Peter

doi:10.1074/jbc.272.8.4804

Cited by 29 publications

(33 citation statements)

References 50 publications

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“…Collective effects have been previously reported for acidic FGF-1 in bladder carcinoma cells (28). Nonlinear effects are likely to be the rule for most biological molecules; the nonlinearity is generally a sigmoid shape described by the Hill equation (29), and examples of sigmoid effects have been reported for IGF-II and other growth factors (24,30,31).…”

Section: Discussionmentioning

confidence: 98%

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Archetti

Ferraro

Christofori

2015

Proc. Natl. Acad. Sci. U.S.A.

147

218

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The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.game theory | tumor | evolution

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Section: Discussionmentioning

confidence: 98%

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Archetti

Ferraro

Christofori

2015

Proc. Natl. Acad. Sci. U.S.A.

147

218

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“…For cancer cells this would imply that proliferation is a linear function of the amount of circulating growth factors, an assumption that is clearly not true; growth rates of cancer cells are typically a sigmoid function of the concentration of growth factors [e.g. : Valenzano et al 1997, Karey & Sirbasku 1988, Jourdan et al 2005. We will assume different types of non-linear benefits here.…”

Section: Growth Factors Are Non-linear Public Goodsmentioning

confidence: 99%

“…The effect of growth factors on cell proliferation has been reported to be a sigmoid function in different types of cancer [e.g. : Valenzano et al 1997, Karey & Sirbasku 1988, Jourdan et al 2005. Non-linearities play a major role in the dynamics of diffusible public goods.…”

Section: The Type Of Non-linear Benefit Is the Main Determinant Of Thmentioning

confidence: 99%

Cooperation among cancer cells as public goods games on Voronoi networks

Archetti

2016

Journal of Theoretical Biology

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Cancer cells produce growth factors that diffuse and sustain tumor proliferation, a form of cooperation among cancer cells that can be studied using mathematical models of public goods in the framework of evolutionary game theory. Cell populations, however, form heterogeneous networks that cannot be described by regular lattices or scale-free networks, the types of graphs generally used in the study of cooperation. To describe the dynamics of growth factor production in populations of cancer cells, I study public goods games on Voronoi networks, using a range of non-linear benefits that account for the known properties of growth factors, and different types of diffusion gradients. The results are surprisingly similar to those obtained on regular graphs and different from results on scale-free networks, revealing that network heterogeneity per se does not promote cooperation when public goods diffuse beyond one-step neighbours. The exact shape of the diffusion gradient is not crucial, however, whereas the type of non-linear benefit is an essential determinant of the dynamics. Public goods games on Voronoi networks can shed light on intra-tumor heterogeneity, the evolution of resistance to therapies that target growth factors, and new types of cell therapy.

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“…Mature IGF-II, a 7.5-kDa peptide containing 67 amino acids, is originally synthesized as a biologically inactive pro-IGF-II peptide (156 amino acids), which subsequently undergoes regulated endoproteolytic cleavage to the mature form. In addition to mature IGF-II, two ''big'' variants, IGF-II (1-87) and IGF-II (1-104), have been identified in human and bovine serum (10)(11)(12)(13). They are 11-17 kDa in size, contain 87 or 104 amino acids, respectively, and differ in glycosylation (10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

“…In addition to mature IGF-II, two ''big'' variants, IGF-II (1-87) and IGF-II (1-104), have been identified in human and bovine serum (10)(11)(12)(13). They are 11-17 kDa in size, contain 87 or 104 amino acids, respectively, and differ in glycosylation (10)(11)(12)(13)(14). It has been suggested that big IGF-II is biologically active but may have different activity in tumor cells when compared with mature IGF-II (15).…”

mentioning

confidence: 99%

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

Qiu

Basak

Mbikay

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth. This growth factor must undergo posttranslational processing, and, thus, we hypothesized that aberrant processing of pro-IGF-II to IGF-II may be a cause of IUGR. Here, we have found that the proprotein convertase PC4 is expressed in the human placenta and that it cleaves pro-IGF-II to generate the intermediate processed form, IGF-II (1-102) and, subsequently, mature IGF-II (1-67), which are accounted for by the removal of terminal basic residues by carboxypeptidases. This processing confers the ability of IGF-II to activate invasive trophoblast cells through AKT phosphorylation, whereas inhibition of PC4 by a PC4-specific inhibitor blocks pro-IGF-II processing and reduces trophoblast cell migration, which can be partly restored by addition of mature IGF-II. Consistent with the hypothesis that IGF-II processing is implicated in IUGR, sera of patients carrying IUGR fetuses displayed elevated levels of pro-IGF-II. Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR.insulin-like growth factor II ͉ intrauterine growth restriction

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Biophysical and Biological Properties of Naturally Occurring High Molecular Weight Insulin-like Growth Factor II Variants

Cited by 29 publications

References 50 publications

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Cooperation among cancer cells as public goods games on Voronoi networks

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

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