## 2 Materials and Methods  
A MEDLINE/PubMed database search was performed to identify studies reporting the role of exosomal Hsps (small Hsps, Hsp40, Hsp60, Hsp70 and Hsp90 families) in selected AYA cancers. The following key words were searched together with their appropriate synonyms, abbreviations and MeSH terms: \"heat shock proteins\" and \"chaperones\" combined with \"exosomes\" and \"extracellular vesicles\". All terms were searched in selected AYA neoplasms: carcinomas of the thyroid, breast, cervix, endometrium, ovary, colon, liver, lung, melanoma and malignant CNS tumors. The search was limited to manuscripts published in English from I' 1990 to V' 2020. The reference lists in all publications were also searched for additional studies. Articles in languages other than English, studies analyzing exosomal Hsps in benign diseases and malignancies not included in this review, studies analyzing the exosome-detection methodology only, studies not defining the precise location of analyzed Hsps and reviews were excluded from analysis. Summary of the methodology of the exosomes' determination and the clinical values of reviewed studies is presented in Table 1 and in Figure 1.  
Figure 1: Summary of the methodology of the exosomes’ determination and the clinical values of reviewed studies. \begin{table}
\begin{tabular}{l l l l l l} \hline \hline
**Cancer Type** & **Analyzed Material** & **Exosomal Hsps** & **Clinical Values** & **Location** & **References** \\ \hline CNS & & & & & \\ \hline glioma, glioblastoma & & & & & \\ multiforme, murine & cell lines & Hsp27, Hsp0, Hsp70, & - & not mentioned & [57,136] \\  & analysiset astrocytoma & & & & \\ \hline glioblastoma multiforme & cell line & Hsp90x & increase in tumor cells motility by activating plasmin; & not mentioned & [88] \\  & & & & tumor progression and metastasis formation & [88] \\ \hline glioblastoma multiforme & human tumor tissue & Hsp70 & antitumor immunontulation (induction of glioma-specific cytotoxic CD8+ T-cells response) & not mentioned & [99] \\ \hline Melanoma & & & & \\ \hline - & cell lines, human plasma & Hsp70, Hsp90 & possible use as a diagnostic marker & not mentioned & [99,137,138] \\ \hline - & human ascites aspartate & Hsp70, Hsp80 & - & not mentioned & [102] \\ \hline - & mice tumor tissue & Hsp70 & inhibition of melanoma progression and dissemination via activation of NK cells & erosomal surface & [90] \\ \hline - & cell line & Hsp70 & inhibition of antitumor immune response via activation of the myeloid-derived suppressor cells & erosomal surface & [95] \\ \hline Colorectal carcinoma & & & & \\ \hline - & human blood & Hsp0 & possible biomarker of recurrence & erosomal surface & [100] \\ \hline - & cell lines, human ascites & Hsp70 & Induction of anti-tumor immune response via activation of NK cells and Hsp70-dependent IL-6 & [99,159]not mentioned & [99,192,95] \\  & aspitate & & secretion from dendritic cells & [92] & \\ \hline \hline \end{tabular}
\begin{tabular}{l l l l} \hline \hline  & & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\ \hline Hepatocellular carcinoma & & & & \\ \hline - & cell line & Hsp70 & - & not mentioned & [140] \\ \hline - & cell line & Hsp70 & promotion of angiogenesis, immune response & erosomal surface & [93] \\ \hline - & cell line & Hsp0, Hsp70, Hsp90 & enhancement ofosomal Hsps release under chemotherapy treatment, activation of NK cells & erosomal surface & [129] \\  & & & resulting in stronger antitumor immune response & \\ \hline - & cell line & Hsp70 & upregulation of erosomal Hsp70 secretion and enhancement of NK-mediated immune response as a result of treatment with the epigenetic drug MS-275 & erosomal surface & [94] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Summary of the methodology of the exosomes determination and their clinical values.