## 3 Generation of a Cachexia-Induced Phenotype
### Cancer Cells' Secreted Factors
\begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Cell Line** & **Induction Method** & **Cell Effect** & \begin{tabular}{c} **Mechanism of** \\ **Action** \\ \end{tabular} & **References** \\ \hline \multirow{4}{*}{**C2C12**} & Microvesicles from A549, & \multirow{4}{*}{Increased apoptosis} & Expression of miR-21, signalling & \multirow{4}{*}{[85; 90]} \\  & PANC-1 and A549 cell lines & & through the Toll-like 7 & & \\  & & & receptor (TLR7) & \\ \cline{2-5}  & miR-195a-5p and & & & & \\  & miR-125b-1-3p mimics & & Increased apoptosis & Bcl-2-mediated apoptosis & [85] \\ \hline \multirow{4}{*}{**L6**} & Conditioned medium from & Reduction of insulin & Downregulation of & \multirow{4}{*}{[91]} \\  & MCF7 and BT474 & responsiveness & PI3-kinase/PKB pathway & & \\ \cline{2-5}  & & Protein degradation; & & \\  & Dexamethasone (1 \(\upmu\)M for 6 h) & increased expression of & Downregulation of NF-\(\upkappa\)B & \\  & & ubiquitin and & signalling pathway & \\  & & proteosome proteins & & \\ \cline{2-5}  & Doxorubicin (0 to 1 \(\upmu\)Mol & Decrease in glucose uptake & Reduction of AMPK activity & [93] \\  & for 48) & & & \\ \hline \multirow{4}{*}{**HSMC**} & Conditioned medium from & Reduction in myotubes & Cannabinoid receptors (CB1R & \multirow{4}{*}{[94]} \\  & SW480 and H1299 cell lines & number and diameter & and CB2R) & \\ \cline{2-5}  & Methylprednisolone & Increased expression of & \multirow{4}{*}{NF-\(\upkappa\)B-inducing kinase (NIK)} & \\  & (0.5 ug/mL for 24 h) & Atrogin-1 and Murf1 & & \\ \hline \multirow{4}{*}{**H95C2**} & \multirow{4}{*}{\begin{tabular}{c} Ascites from CT26-induced \\ cachexia mice model \\ \end{tabular} } & Reduction of cell & \multirow{4}{*}{\begin{tabular}{c} Expression of TNF-\(\upalpha\) and high \\ and ATP production; \\ increase in oxidative stress \\ \end{tabular} } & \\  & & Reduction of cell & \multirow{4}{*}{\begin{tabular}{c} Expression of TNF-\(\upalpha\) and high \\ mobility group box (HMGB1) \\ \end{tabular} } & \\  & Ascites from CT26-induced & mitochondrial respiration & & \\  & cachexia mice model & & & \\  & & and ATP production; & & \\  & & increase in oxidative stress & & \\ \cline{2-5}  & TNF-\(\upalpha\), IFN-\(\upgamma\), IL-6, IL-8, and & Increase in mitochondrial & \multirow{4}{*}{\begin{tabular}{c} Upregulation of \\ dynamin-related protein 1 \\ (DRP1) and the mitochondrial \\ outer membrane protein (hFIS1) \\ \end{tabular} } & \\  & IL-1\(\upbeta\) (50 ng/mL for 48h) & & & \\ \hline \multirow{4}{*}{**3T3-L1**} & LLC cell-derived & Adipocyte lipolysis and & \multirow{4}{*}{\begin{tabular}{c} Parathyroid hormone-related \\ protein (PTHrp) mediated \\ protein kinase A (PKA) pathway \\ \end{tabular} } & \\  & extracellular vesicles from C26 & & & \\ \cline{2-5}  & cells (3.12–100 \(\upmu\)M for 48 h) & Adipocyte lipolysis & \multirow{4}{*}{\
\begin{tabular}{c} Upregulation of STAT3/PKM2/ \\ SNAP23 pathway \\ \end{tabular} } & \\  & and IL-6 & & & \\ \cline{2-5}  & Breast cancer derived & Increase in adipocyte & \multirow{4}{*}{
\begin{tabular}{c} Hypoxia-inducible factor 1A \\ (HIF1A) induced by leptin \\ signalling pathway \\ \end{tabular} } & \\  & extracellular vesicles & lipidysis and & & \\  & (miR-204-5p) & WAT browning & signalling pathway & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: _Cont._myotubes treated with CM from pancreatic cancer cells release high levels of Hsp70- and Hsp90-induced muscle wasting mediated by p388 MAPK [86].