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J Cancer Metastasis Treat 2019;5:31 I http://dx.doi.org/10.20517/2394-4722.2019.21 Page 12 of 36

cancer hosts was reported. In particular, Pax7+ cells accumulate in the muscle of tumor-bearing animals
without proceeding into differentiation and fusing with existing myofibers. Such impairment was proposed
to depend on persistently expressed Pax7 due to NF-κB hyperactivation. The reduced myogenesis does not
depend on an intrinsic defect of muscle stem cells, since they can easily differentiate in vitro and can fuse
with damaged myofibers in an experimental model of muscle dystrophy. However, myogenic precursors
isolated from mice bearing the C26 tumor cultured in proliferation medium spontaneously differentiate to
adipocytes.

To investigate the mechanisms underlying such “adipogenic drive”, mice bearing the C26 carcinoma were
treated intraperitoneally with IL-4, a cytokine previously shown to inhibit adipogenesis in muscle. The
results obtained show that muscle wasting was partially prevented in tumor-bearing animals receiving IL-
4, in terms of both tissue weight and myofiber cross sectional area. The improved muscle phenotype is
associated with reduced levels of phosphorylated ERK, in agreement with previous data. The spontaneous
adipogenic differentiation is markedly reduced in primary cultures of myogenic precursors isolated from
the C26 hosts treated with IL-4 in comparison to those obtained by untreated animals. This observation
suggested that IL-4, by inhibiting adipogenesis, could force myogenesis. Consistently, when IL-4 is
administered to tumor-bearing animals in which muscle damage was induced by injection of BaCl2,
regeneration occurred faster than in the untreated C26 hosts.

On the whole these results suggest that primary cultures of myogenic precursors isolated from tumor-
bearing animals are committed to differentiate to adipocytes, but can be forced through myogenesis by
adequate stimuli. By contrast, the muscle microenvironment existing in vivo in the tumor host is able to
inhibit both myogenic and adipogenic differentiation of these precursors, that indeed accumulate in the
tissue. Preliminary data suggest that the lack of IL-4 production could play a role in this regard.

16. Lenvatinib in anaplastic thyroid cancer

1
1
1
1
1
Alessandro Antonelli , Silvia Martina Ferrari , Ilaria Ruffilli , Giusy Elia , Francesca Ragusa , Sabrina
1
1
Rosaria Paparo , Claudia Caruso , Poupak Fallahi 2
1 Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy.
2 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa,
Pisa 56126, Italy.
The oral multitargeted tyrosine kinase inhibitor lenvatinib acts against VEGFR1-VEGFR3, FGFR1-FGFR4,
PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling
networks involved in tumor angiogenesis.

The antitumor activity of lenvatinib (1 nmol/L, 100 nmol/L, 1 mcmol/L, 10 mcmol/L, 25 mcmol/L and
50 mcmol/L) has been investigated in primary anaplastic thyroid cancer (ATC) cells, in the human cell
line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF), in vitro; and in vivo in AF cells
injected in CD nu/nu mice.

Lenvatinib significantly reduced ATC cell proliferation (P < 0.01, ANOVA), increasing apoptosis (P <
0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P < 0.01) and invasion (P < 0.001) in ATC,
inhibited EGFR, AKT and ERK1/2 phosphorylation and down-regulated cyclin D1 in ATC cells. Moreover,
lenvatinib significantly inhibited 8305C and AF cell proliferation, increasing apoptosis.