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Rath et al. J Cancer Metastasis Treat 2020;6:30 I http://dx.doi.org/10.20517/2394-4722.2020.51 Page 7 of 10

Figure 6. Comparison of selected proteins of the BHGC7 SCLC CTC cell line and its corresponding BHGc7 MAT. The ARY026 array
used detects 84 cancer-related proteins *significantly different protein amounts are marked with an asterisk. Error bars represent mean
values ± SD. CTC: circulating tumor cell; SCLC: small-cell lung cancer; MAT: material

within approximately 1-2 years, often with a dismal prognosis. Second-line therapy consisting of topotecan
or vincristine-epirubicin-cyclophosphamide regimens results in low response rates of short duration.
Addition of further agents or administration of novel agents yields no major improvement with the
[11]
exception of some progress with immunotherapy in responsive patients .
The genome and gene expression of SCLC tumor tissue has been extensively characterized. Apart from
[3]
inactivation of p53 and RB1, driver kinases have been detected in minor subpopulations of patients .
The major tumor-promoting mechanism appears to be a general transcriptional de-regulation, which is
difficult to target. Chemoresistance to a host of structurally unrelated compounds in SCLC is not feasibly
explained by a matching range of individual counteracting mechanisms and global impairment of cell death
has not been overcome, for example, by Bcl2 inhibitors . Therefore, the most likely mechanism of drug
[12]
resistance remains to be presence of physical resistance at the tumor tissue level. The rapidly advancing
SCLC recurrences may outgrow their vessel supply resulting in tumor cells near the necrotic area becoming
increasingly resistant and aggressive. We have shown previously that SCLC CTCs form large aggregates,
termed tumorospheres, spontaneously in tissue culture and that such spheroids exhibit significantly higher
[7]
levels of resistance to chemotherapeutics as compared to single cell suspensions . Such tumorospheres
may not exist in the circulation, but they form in capillaries prior to extravasation and generation of
[13]
metastases . Furthermore, our collection of SCLC CTCs exhibit shedding of large quantities of cellular
fragments in the presence of intact tumor cells, which can then be cultivated for unlimited passages. For
certain SCLC CTC, such as BHGc7, BHGc10, BHGc16 and UHGc5lines, its fragments are released into
the surrounding media but for other CTC lines as shown in Figure 1, tumor cell aggregates may be covered
by fragments like a complete envelope. This superficially attached cover may be removed with the use of
vigorous pipetting, demonstrating a loose association with cells.

Our present results indicate that the MAT has profound effects on chemosensitivity of SCLC CTC
[14]
and SCLC cell lines through the increase of resistance to topotecan to a large degree . This effect is