Search

Background and objectives. During the two past decades, a new therapeutic approach to ovarian cancer (OC) has been developed. This combines cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, almost no data exist regarding the utility of biomarkers of morphological heterogeneity as prognostic factors in such patients. Methods. A retrospective study of the effectiveness of CRS and HIPEC was carried out in 59 patients with ovarian cancer. Biomarkers of morphological heterogeneity of OC were studied as prognostic factors: OC pathogenic types (based on the identification of р53 mutated gene protein expression) and homologous recombination deficit (basing on the identification of BRCA 1 gene expression status). Results. The survival of patients reliably differed with the division into two pathogenetic OC types established by immunohistochemistry: the median disease-free survival of type I OC patients was 14±1.7 months, type ІІ – 8±1.6 months (р = 0.007); the median overall survival of type I OC patients was 23.5±6.7 months, type ІІ – 12±1.9 months (р = 0.017). The median overall survival of patients with the somatic mutation of BRCA 1 gene and complete cytoreduction was 22±4.8 months, and without the somatic mutation of BRCA 1 gene – 12±3.3 months (р = 0.047). Conclusions. These data demonstrate that identification of the pathogenetic type of OC and BRCA 1 status may be useful for the personalized therapy of ovarian cancer patients treated with CRS/HIPEC.

Tumor-associated macrophages (TAMs) are prominent components of tumor stroma that promotes tumorigenesis. Many soluble factors participate in the deleterious cross-talk between TAMs and transformed cells; however mechanisms how tumors orchestrate their production remain relatively unexplored. c-Myb is a transcription factor recently described as a negative regulator of a specific immune signature involved in breast cancer (BC) metastasis. Here we studied whether c-Myb expression is associated with an increased presence of TAMs in human breast tumors. Tumors with high frequency of c-Myb-positive cells have lower density of CD68-positive macrophages. The negative association is reflected by inverse correlation between MYB and CD68/CD163 markers at the mRNA levels in evaluated cohorts of BC patients from public databases, which was found also within the molecular subtypes. In addition, we identified potential MYB-regulated TAMs recruiting factors that in combination with MYB and CD163 provided a valuable clinical multigene predictor for BC relapse. We propose that identified transcription program running in tumor cells with high MYB expression and preventing macrophage accumulation may open new venues towards TAMs targeting and BC therapy.

Adaptor proteins play an important role in facilitating protein-protein interactions and subsequent formation of signalling networks. These proteins recruit binding partners to a specific location inside the cell, and also regulate their activity. Adaptor protein Ruk/CIN85 and its structural and functional homologue CD2AP/CMS are important components of different regulatory pathways involved in control of cell proliferation, adhesion, invasion and survival, and, thus, can play a role in uterine carcinogenesis. In this work, we set out a comparative study of expression of Ruk/CIN85 and CD2AP/CMS at the level of mRNA and protein in intact uterine tissues, as well as in benign and malignant uterine tumors of different histological types. In most cases, an increase of expression levels of Ruk/CIN85 full-length form mRNA and protein, as well as CD2AP/CMS protein, were observed in uterine tumors, comparing with surrounding normal uterine tissues. Characteristic feature of conditionally normal uterine tissues, as well as benign uterine lesions, was an elevated content of high-molecular mass Ruk/CIN85 forms of 140 and 130 kDa, while an increased expression level of low-molecular mass 40 and 30 kDa Ruk/CIN85 forms was observed in the malignant tissue samples. Our findings suggest that an abnormal expression patterns of adaptor proteins Ruk/CIN85 and CD2AP/CMS in uterine tumors, and, thus, the corresponding changes in the activity of downstream signalling pathways, might be involved in maintenance of the malignant phenotype.

The adaptor protein regulator for ubiquitous kinase/c-Cbl-interacting protein of 85kDa (Ruk/CIN85) was found to modulate HER1/EGFR signaling and processes like cell adhesion and apoptosis. Although these features imply a role in carcinogenesis, it is so far unknown how and by which molecular mechanisms Ruk/CIN85 could affect a certain tumor phenotype. By analyzing samples from breast cancer patients, we found high levels of Ruk(l)/CIN85 especially in lymph node metastases from patients with invasive breast adenocarcinomas, suggesting that Ruk(l)/CIN85 contributes to malignancy. Expression of Ruk(l)/CIN85 in weakly invasive breast adenocarcinoma cells deficient of Ruk(l)/CIN85 indeed converted them into more malignant cells. In particular, Ruk(l)/CIN85 reduced the growth rate, decreased cell adhesion, enhanced anchorage-independent growth, increased motility in both transwell migration and wound healing assays as well as affected the response to epidermal growth factor. Thereby, Ruk(l)/CIN85 led to a more rapid and prolonged epidermal growth factor-dependent activation of Src, Akt and ERK1/2 and treatment with the Src inhibitor PP2 and the PI3K inhibitor LY294002 abolished the Ruk(l)/CIN85-dependent changes in cell motility. Together, this study indicates that high levels of Ruk(l)/CIN85 contribute to the conversion of breast adenocarcinoma cells into a more malignant phenotype via modulation of the Src/Akt pathway.