14
Hepatology. 2013Jul 6.
Organized proteomic heterogeneity in colorectal cancer liver
metastasesand implications for therapies.
Turtoi A, BlommeA, DeboisD, SomjaJ, DelvauxD, PatsosG, Di ValentinE, PeulenO,MutijimaEN,
DePauwE, DelvenneP, DetryO, CastronovoV.
Abstract
Tumor heterogeneity is amajor obstacle for developing effective anticancer treatments. Recent
studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where
no pattern seems to exist that would enable a more structured targeted therapy approach.
Because todatenosimilar information isavailableat theprotein (phenotype) level, weemployed
matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the
heterogeneity of extracellular andmembrane subproteome in a unique collection of eight fresh
human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over
1,000 proteins, we foundunexpectedly that all livermetastasis lesions displayed a reproducible,
zonally delineatedpatternof functional and therapeuticbiomarker heterogeneity. The peritumo-
ral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis
displayed increasedcellular growth,movement, anddrugmetabolism, whereas thecenter of the
lesionwascharacterizedbyelevatedcarbohydratemetabolismandDNA-repairactivity. From the
aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident,
reinforcing the need to select several targets in order to achieve optimal coverage of the lesion.
Finally, wehighlight twonovel antigens, LTBP2andTGFBI, whoseexpression isaconsistent fea-
tureofCRC livermetastasis.Wedemonstrate their invivoantibody-based targetingandhighlight
their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of
humanCRC livermetastaseshasadistinct, organizedpattern. Thisparticular hallmark cannow
beusedaspart of thestrategy for developing rational therapiesbasedonmultiplesetsof targe-
tableantigens.
Angiogenesis. 2013Apr;16(2):353-71.
Newprospects in the rolesof theC-terminal domainsofVEGF-
A and their cooperation for ligand binding, cellular signaling
andvessels formation.
Delcombel R, Janssen L, Vassy R, Gammons M, Haddad O, Richard B, Letourneur D, Bates D,
HendricksC,Waltenberger J, StarzecA, Sounni NE, Noël A, DeroanneC, Lambert C, ColigeA.
Abstract
VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis.
Due toalternativesplicingof itspre-mRNA, VEGF-A isproducedunder several isoformscharac-
terizedby thecombinationof theirC-terminal domains, whichdetermines their respectivestruc-
ture, availability and affinity for co-receptors. As controversies still exist about the specific roles
of theseexon-encodeddomains,wesystematicallycompared thepropertiesof eight natural and
artificial variantscontaining thedomainsencodedbyexons1-4andvariouscombinationsof the
domainsencodedbyexons5, 7and8aor 8b. All the variants (VEGF111a, VEGF111b, VEGF121a,
VEGF121b, VEGF155a, VEGF155b, VEGF165a, VEGF165b) have a similar affinity for VEGF-R2,
as determined by Surface plasmon resonance analyses. They strongly differ however in terms
of binding to neuropilin-1 and heparin/heparan sulfate proteoglycans. Data indicate that the 6
amino acids encoded by exon 8amust be present and cooperatewith those of exons 5 or 7 for
efficient binding, whichwasconfirmed incell culturemodels.We further showed that VEGF165b
has inhibitory effects
in vitro
, as previously reported, but that the shortest VEGF variant pos-
sessing also the 6 amino acids encoded by exon 8b (VEGF111b) is remarkably proangiogenic,
demonstrating the critical importance of domain interactions for defining the VEGF properties.
Thenumber, size and localizationof newly formedblood vessels inamodel of tumour angioge-
nesis strongly depend also on the C-terminal domain composition, suggesting that association
of several VEGF isoformsmay bemore efficient for treating ischemic diseases than the use of
anysinglevariant.
