Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.
Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia.
J Exp Clin Cancer Res. 2021 Sep 27;40(1):302. doi: 10.1186/s13046-021-02087-2.
Chemotherapy remains a standard treatment option for breast cancer despite its toxic effects to normal tissues. However, the long-lasting effects of chemotherapy on non-malignant cells may influence tumor cell behavior and response to treatment. Here, we have analyzed the effects of doxorubicin (DOX) and paclitaxel (PAC), commonly used chemotherapeutic agents, on the survival and cellular functions of mesenchymal stromal cells (MSC), which comprise an important part of breast tumor microenvironment.
Chemotherapy-exposed MSC (DOX-MSC, PAC-MSC) were co-cultured with three breast cancer cell (BCC) lines differing in molecular characteristics to study chemotherapy-triggered changes in stromal compartment of the breast tissue and its relevance to tumor progression in vitro and in vivo. Conditioned media from co-cultured cells were used to determine the cytokine content. Mixture of BCC and exposed or unexposed MSC were subcutaneously injected into the immunodeficient SCID/Beige mice to analyze invasion into the surrounding tissue and possible metastases. The same mixtures of cells were applied on the chorioallantoic membrane to study angiogenic potential.
Therapy-educated MSC differed in cytokine production compared to un-exposed MSC and influenced proliferation and secretory phenotype of tumor cells in co-culture. Histochemical tumor xenograft analysis revealed increased invasive potential of tumor cells co-injected with DOX-MSC or PAC-MSC and also the presence of nerve fiber infiltration in tumors. Chemotherapy-exposed MSC have also influenced angiogenic potential in the model of chorioallantoic membrane.
Data presented in this study suggest that neoadjuvant chemotherapy could possibly alter otherwise healthy stroma in breast tissue into a hostile tumor-promoting and metastasis favoring niche. Understanding of the tumor microenvironment and its complex net of signals brings us closer to the ability to recognize the mechanisms that prevent failure of standard therapy and accomplish the curative purpose.
尽管化疗对正常组织具有毒性作用，但它仍然是乳腺癌的标准治疗选择。然而，化疗对非恶性细胞的长期影响可能会影响肿瘤细胞的行为和对治疗的反应。在这里，我们分析了多柔比星（DOX）和紫杉醇（PAC）这两种常用化疗药物对间充质基质细胞（MSC）存活和细胞功能的影响，MSC 是乳腺肿瘤微环境的重要组成部分。
将化疗暴露的 MSC（DOX-MSC、PAC-MSC）与三种具有不同分子特征的乳腺癌细胞（BCC）系共培养，以研究化疗对乳腺组织基质区室的触发变化及其与体内外肿瘤进展的相关性。共培养细胞的条件培养基用于测定细胞因子含量。将 BCC 与暴露或未暴露的 MSC 的混合物皮下注射到免疫缺陷 SCID/Beige 小鼠中，以分析其对周围组织的侵袭和可能的转移。将相同的细胞混合物应用于绒毛尿囊膜上，以研究其血管生成潜力。
与未暴露的 MSC 相比，经治疗教育的 MSC 在细胞因子产生方面存在差异，并影响共培养中的肿瘤细胞的增殖和分泌表型。组织化学肿瘤异种移植分析显示，与 DOX-MSC 或 PAC-MSC 共注射的肿瘤细胞侵袭潜力增加，肿瘤中也存在神经纤维浸润。化疗暴露的 MSC 也影响了绒毛尿囊膜模型中的血管生成潜力。
本研究提供的数据表明，新辅助化疗可能会改变乳腺组织中原本健康的基质，使其成为促进肿瘤生长和有利于转移的恶性基质。对肿瘤微环境及其复杂信号网络的理解使我们更接近于识别阻止标准治疗失败并实现治疗目的的机制的能力。
