Gawin Marta, Kurczyk Agata, Niemiec Joanna, Stanek-Widera Agata, Grela-Wojewoda Aleksandra, Adamczyk Agnieszka, Biskup-Frużyńska Magdalena, Polańska Joanna, Widłak Piotr
Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland.
Maria Skłodowska-Curie National Research Institute of Oncology, Kraków Branch, 31-115 Kraków, Poland.
Cancers (Basel). 2021 Aug 27;13(17):4349. doi: 10.3390/cancers13174349.
Intra-tumor heterogeneity (ITH) results from the coexistence of genetically distinct cancer cell (sub)populations, their phenotypic plasticity, and the presence of heterotypic components of the tumor microenvironment (TME). Here we addressed the potential association between phenotypic ITH revealed by mass spectrometry imaging (MSI) and the prognosis of breast cancer. Tissue specimens resected from 59 patients treated radically due to the locally advanced HER2-positive invasive ductal carcinoma were included in the study. After the on-tissue trypsin digestion of cellular proteins, peptide maps of all cancer regions (about 380,000 spectra in total) were segmented by an unsupervised approach to reveal their intrinsic heterogeneity. A high degree of similarity between spectra was observed, which indicated the relative homogeneity of cancer regions. However, when the number and diversity of the detected clusters of spectra were analyzed, differences between patient groups were observed. It is noteworthy that a higher degree of heterogeneity was found in tumors from patients who remained disease-free during a 5-year follow-up ( = 38) compared to tumors from patients with progressive disease (distant metastases detected during the follow-up, = 21). Interestingly, such differences were not observed between patients with a different status of regional lymph nodes, cancer grade, or expression of estrogen receptor at the time of the primary treatment. Subsequently, spectral components with different abundance in cancer regions were detected in patients with different outcomes, and their hypothetical identity was established by assignment to measured masses of tryptic peptides identified in corresponding tissue lysates. Such differentiating components were associated with proteins involved in immune regulation and hemostasis. Further, a positive correlation between the level of tumor-infiltrating lymphocytes and heterogeneity revealed by MSI was observed. We postulate that a higher heterogeneity of tumors with a better prognosis could reflect the presence of heterotypic components including infiltrating immune cells, that facilitated the response to treatment.
肿瘤内异质性（ITH）源于基因不同的癌细胞（亚）群的共存、它们的表型可塑性以及肿瘤微环境（TME）中异型成分的存在。在此，我们探讨了通过质谱成像（MSI）揭示的表型ITH与乳腺癌预后之间的潜在关联。本研究纳入了59例因局部晚期HER2阳性浸润性导管癌而接受根治性治疗的患者的组织标本。对细胞蛋白进行组织上的胰蛋白酶消化后，采用无监督方法对所有癌区的肽图谱（总共约380,000个光谱）进行分割，以揭示其内在异质性。观察到光谱之间具有高度相似性，这表明癌区具有相对同质性。然而，当分析检测到的光谱簇的数量和多样性时，发现患者组之间存在差异。值得注意的是，与疾病进展的患者（随访期间检测到远处转移，n = 21）的肿瘤相比，在5年随访期间无疾病复发的患者（n = 38）的肿瘤中发现了更高程度的异质性。有趣的是，在初次治疗时区域淋巴结状态、癌症分级或雌激素受体表达不同的患者之间未观察到此类差异。随后，在不同预后的患者中检测到癌区中丰度不同的光谱成分，并通过将其与相应组织裂解物中鉴定出的胰蛋白酶肽的测量质量进行比对来确定其假定身份。此类区分性成分与参与免疫调节和止血的蛋白质相关。此外，观察到肿瘤浸润淋巴细胞水平与MSI揭示的异质性之间呈正相关。我们推测，预后较好的肿瘤具有更高的异质性可能反映了包括浸润免疫细胞在内的异型成分的存在，这促进了对治疗的反应。
