Formation Of Distant Metastases Research Articles

Targeting the gut and tumor microbiome in cancer resistance.

Therapy resistance represents a significant challenge in oncology, occurring in various therapeutic approaches. Recently, animal models and an increasing set of clinical trials highlight the crucial impact of the gut and tumor microbiome on treatment response. The intestinal microbiome contributes to cancer initiation, progression, and formation of distant metastasis. In addition, tumor-associated microbiota is considered a critical player in influencing tumor microenvironment and regulating local immune processes. Intriguingly, numerous studies have successfully identified pathogens within the gut and tumor microbiome that might be linked to a poor response to different therapeutic modalities. The unfavorable microbial composition with the presence of specific microbes participates in cancer resistance and progression via several mechanisms, including upregulation of oncogenic pathways, macrophage polarization reprogramming, metabolism of chemotherapeutic compounds, autophagy pathway modulation, enhanced DNA damage repair, inactivation of a pro-apoptotic cascade, and bacterial secretion of extracellular vesicles, promoting the processes in the metastatic cascade. Targeted elimination of specific intratumoral bacteria appears to enhance treatment response. However, broad-spectrum antibiotic pre-treatment is mostly connected to reduced efficacy due to gut dysbiosis and lower diversity. Mounting evidence supports the potential of microbiota modulation by probiotics and fecal microbiota transplantation to improve intestinal dysbiosis and increase microbial diversity, leading to enhanced treatment efficacy while mitigating adverse effects. In this context, further research concerning the identification of clinically relevant microbiome signatures followed by microbiota-targeted strategies presents a promising approach to overcoming immunotherapy and chemotherapy resistance in refractory patients, improving their outcomes.

Abstract 1566: Cancer metastasis and stemness: The metastasis-inducer MACC1 regulates LGR5 to promote cancer stem cell-like properties in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease which is thought to be initiated by colon cancer stem cells according to cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcome. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and CSC-associated invasive phenotype based on patient-derived 3D cell culture models (PD3D), patient-derived xenografts (PDX) and human CRC cell lines. We showed that CD44-enriched CSCs from PD3D models express significantly higher levels of MACC1 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PD3D and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with CSC markers CD44, NANOG and LGR5 in PD3D models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter uncovering the long-known CSC marker LGR5 as novel essential signaling mediator used by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by significant positive correlation of MACC1 and LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis-inducer MACC1 act as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs, prevent cancer recurrence and distant metastasis formation. Citation Format: Müge Erdem, Kyung Hwan Lee, Markus Hardt, Joseph Regan, Dennis Kobelt, Wolfgang Walther, Christian Regenbrecht, Ulrike S. Stein. Cancer metastasis and stemness: The metastasis-inducer MACC1 regulates LGR5 to promote cancer stem cell-like properties in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1566.

Suppression of the growth and metastasis of mouse melanoma by Taenia crassiceps and Mesocestoides corti tapeworms.

Cancer is still one of the leading causes of death, with an estimated 19.3 million new cases every year. Our paper presents the tumor-suppressing effect of Taenia crassiceps and Mesocestoides corti on B16F10 melanoma, the intraperitoneal application of which followed the experimental infection with these tapeworms, resulting in varying degrees of effectiveness in two strains of mice. In the case of M. corti-infected ICR mice, a strong tumor growth suppression occurred, which was accompanied by a significant reduction in the formation of distant metastases in the liver and lung. Tapeworm-infected C57BL/6J mice also showed a suppression of tumor growth and, in addition, the overall survival of infected C57BL/6J mice was significantly improved. Experiments with potential cross-reaction of melanoma and tapeworm antigens with respective specific antibodies, restimulation of spleen T cells, or the direct effect of tapeworm excretory-secretory products on melanoma cells in vitro could not explain the phenomenon. However, infections with T. crassiceps and M. corti increased the number of leukocytes possibly involved in anti-tumor immunity in the peritoneal cavity of both ICR and C57BL/6J mice. This study unveils the complex interplay between tapeworm infections, immune responses, and melanoma progression, emphasizing the need for further exploration of the mechanisms driving observed tumor-suppressive effects.

Hypoxia induced exosomal Circ-ZNF609 promotes pre-metastatic niche formation and cancer progression via miR-150-5p/VEGFA and HuR/ZO-1 axes in esophageal squamous cell carcinoma

Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.

Ovarian cancer cells regulate their mitochondrial content and high mitochondrial content is associated with a poor prognosis

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patient’s prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers (n = 155), borderline tumours (n = 24) and recurrent ovarian cancers (n = 26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low (n = 26), intermediate (n = 50) and high (n = 84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice.In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells.

Exploring the Role of the Gut and Intratumoral Microbiomes in Tumor Progression and Metastasis.

Cancer cell dissemination involves invasion, migration, resistance to stressors in the circulation, extravasation, colonization, and other functions responsible for macroscopic metastases. By enhancing invasiveness, motility, and intravasation, the epithelial-to-mesenchymal transition (EMT) process promotes the generation of circulating tumor cells and their collective migration. Preclinical and clinical studies have documented intensive crosstalk between the gut microbiome, host organism, and immune system. According to the findings, polymorphic microbes might play diverse roles in tumorigenesis, cancer progression, and therapy response. Microbial imbalances and changes in the levels of bacterial metabolites and toxins promote cancer progression via EMT and angiogenesis. In contrast, a favorable microbial composition, together with microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), can attenuate the processes of tumor initiation, disease progression, and the formation of distant metastases. In this review, we highlight the role of the intratumoral and gut microbiomes in cancer cell invasion, migration, and metastatic ability and outline the potential options for microbiota modulation. As shown in murine models, probiotics inhibited tumor development, reduced tumor volume, and suppressed angiogenesis and metastasis. Moreover, modulation of an unfavorable microbiome might improve efficacy and reduce treatment-related toxicities, bringing clinical benefit to patients with metastatic cancer.

Development and validation of a circulating tumor cells-related signature focusing on biochemical recurrence and immunotherapy response in prostate cancer

BackgroundStudies have shown that the circulating tumor cells (CTCs) play a key role for invasion and formation of distant metastases in prostate cancer (PCa). However, few CTCs-related genes (CRGs) have been developed for biochemical recurrence (BCR) prediction and clinical applications of PCa patients. Materials and methodsBioinformatics analysis with public PCa datasets were used to investigate the relationship between the differentially expressed CRGs and BCR. Lasso-COX regression analysis was used to constructed and validated a CRGs-based BCR prediction signature for PCa. Single-cell data were used to validate the expression levels of signature genes in different cell types and then explored the cell-cell communication relationships. Finally, the expression levels of signature genes were verified and the CRGs involved in immunotherapy response were further identified. ResultsThirteen CRGs were differentially expressed and closely associated with BCR in PCa. Then we constructed and validated a BCR prediction signature for PCa patients based on 3 differentially expressed CRGs (EMID1, SPP1 and UBE2C), and the signature was an independent factor to predict BCR for PCa. Single-cell data showed the specific expression patterns of the signature genes, while the SPP1 pathway plays an important role in cell-cell communication. Further analyses suggested UBE2C was highly expressed in BCR group and high expression of UBE2C had a better response for patients who received immunotherapy. Moreover, the expression levels of UBE2C in CTCs were higher than other cells and tissues, indicated that UBE2C may affect the BCR event of PCa patients through CTCs. ConclusionOur findings demonstrated that CRGs were significantly associated with BCR and immunotherapy efficacy in PCa and CRGs may influence the BCR event through CTCs.

Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report

BackgroundHematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis.Case presentationWe report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment.ConclusionsE-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.

КАРЦИНОМА ИЗ КЛЕТОК МЕРКЕЛЯ: СОВРЕМЕННЫЕ ТЕНДЕНЦИИ ВРАЧЕБНОЙ ПРАКТИКИ

Merkel cell carcinoma (CM) is a rare but very dangerous (rapidly progressive) malignancy. The need for early detection of CM determines the importance and relevance of informing dermatologists, cosmetologists, doctors of other specialties about the current aspects of the diagnosis and treatment of this disease, despite its relatively rare occurrence. The review highlights modern approaches to the diagnosis and treatment of CM. Early treatment of CM is vital because the disease progresses extremely rapidly with the formation of distant metastases. For the treatment of CM at localized stages, positive results in terms of prognosis in patients are brought by the use of the standard of combined treatment: surgery with adjuvant radiation therapy. A good alternative is also to use of RT only. Effective therapy for late variants of CM includes the appointment of immune response checkpoint inhibitors. Immunotherapy provides a sustained response in a significant proportion of patients with metastatic or recurrent disease. However, in the population of elderly and debilitated patients, the use of immunotherapy is limited due to the development of adverse events. The tasks of determining the optimal therapy regimens with the best efficacy and drug safety profiles have been included in the programs for further clinical research and development.

The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential.

Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.

Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation

BackgroundIncreasing evidence suggests a vital role of the pre-metastatic niche in the formation of distant metastasis of many cancers. However, how the pre-metastatic niche is formed and promotes pulmonary metastasis of hepatocellular carcinoma (HCC) remains unknown.MethodsOrthotopic liver tumor models and RNA-Seq were used to identify dysregulated genes in the pre-metastatic lung. Il1b knockout (Il1b−/−) mice and lentivirus-mediated gene knockdown/overexpression were utilized to demonstrate the role of interleukin 1 beta (IL-1β)/serum amyloid A3 (SAA3) in the pre-metastatic niche formation and pulmonary metastasis. The potential molecular mechanisms were investigated by RNA-Seq, real-time quantitative PCR (qPCR), western blotting, immunohistochemistry (IHC), flow cytometry, luciferase reporter assay, double immunofluorescent staining and H&E staining.ResultsAccumulation of myeloid cells and upregulation of IL-1β were observed in the pre-metastatic lung of orthotopic liver tumor models. Myeloid cells accumulation and pulmonary metastasis were suppressed in Il1b−/− mice and Il1r1-silencing mice. Mechanistically, SAA3 and matrix metallopeptidase 9 (MMP9) were identified as potential downstream targets of IL-1β. Overexpression of SAA3 in the lungs of Il1b−/− mice restored myeloid cells accumulation and pulmonary metastasis of the orthotopic HCC xenografts. Moreover, alveolar macrophages-derived IL-1β dramatically enhanced SAA3 expression in alveolar epithelial cells in an NF-κB dependent manner and increased MMP9 levels in an autocrine manner. Furthermore, SAA3 recruited myeloid cells to the lung without affecting the expression of MMP9 in myeloid cells.ConclusionsOur study suggests a key role of pulmonary IL-1β and SAA3 in creating a permissive lung pre-metastatic niche by enhancing MMP9 expression and recruiting myeloid cells, respectively, thus promoting pulmonary metastasis of HCC.

SFRP1 Expression is Inversely Associated With Metastasis Formation in Canine Mammary Tumours

BackgroundCanine mammary tumours (CMTs) are the most frequent tumours in intact female dogs and show strong similarities with human breast cancer. In contrast to the human disease there are no standardised diagnostic or prognostic biomarkers available to guide treatment. We recently identified a prognostic 18-gene RNA signature that could stratify human breast cancer patients into groups with significantly different risk of distant metastasis formation. Here, we assessed whether expression patterns of these RNAs were also associated with canine tumour progression.MethodA sequential forward feature selection process was performed on a previously published microarray dataset of 27 CMTs with and without lymph node (LN) metastases to identify RNAs with significantly differential expression to identify prognostic genes within the 18-gene signature. Using an independent set of 33 newly identified archival CMTs, we compared expression of the identified prognostic subset on RNA and protein basis using RT-qPCR and immunohistochemistry on FFPE-tissue sections.ResultsWhile the 18-gene signature as a whole did not have any prognostic power, a subset of three RNAs: Col13a1, Spock2, and Sfrp1, together completely separated CMTs with and without LN metastasis in the microarray set. However, in the new independent set assessed by RT-qPCR, only the Wnt-antagonist Sfrp1 showed significantly increased mRNA abundance in CMTs without LN metastases on its own (p = 0.013) in logistic regression analysis. This correlated with stronger SFRP1 protein staining intensity of the myoepithelium and/or stroma (p < 0.001). SFRP1 staining, as well as β-catenin membrane staining, was significantly associated with negative LN status (p = 0.010 and 0.014 respectively). However, SFRP1 did not correlate with β-catenin membrane staining (p = 0.14).ConclusionThe study identified SFRP1 as a potential biomarker for metastasis formation in CMTs, but lack of SFRP1 was not associated with reduced membrane-localisation of β-catenin in CMTs.

Modulation of E-Cadherin Function through the AmotL2 Isoforms Promotes Ameboid Cell Invasion.

The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining cell-cell contacts. Furthermore, the inactivation of E-cadherin triggers invasion in vitro. However, the role of E-cadherin is complex, as metastasizing cells maintain E-cadherin expression, which appears to have a positive role in the survival of tumor cells. In this report, we present a novel mechanism delineating how E-cadherin function is modulated to promote invasion. We have previously shown that E-cadherin is associated with p100AmotL2, which is required for radial actin formation and the transmission of mechanical force. Here, we present evidence that p60AmotL2, which is expressed in invading tumor cells, binds to the p100AmotL2 isoform and uncouples the mechanical constraint of radial actin filaments. We show for the first time that the coupling of E-cadherin to the actin cytoskeleton via p100AmotL2 is directly connected to the nuclear membrane. The expression of p60AmotL2 inactivates this connection and alters the properties of the nuclear lamina, potentiating the invasion of cells into micropores of the extracellular matrix. In summary, we propose that the balance of the two AmotL2 isoforms is important in the modulation of E-cadherin function and that an imbalance of this axis promotes ameboid cell invasion.

A transcriptomic pan-cancer signature for survival prognostication and prediction of immunotherapy response based on endothelial senescence

BackgroundThe microvascular endothelium inherently controls nutrient delivery, oxygen supply, and immune surveillance of malignant tumors, thus representing both biological prerequisite and therapeutic vulnerability in cancer. Recently, cellular senescence emerged as a fundamental characteristic of solid malignancies. In particular, tumor endothelial cells have been reported to acquire a senescence-associated secretory phenotype, which is characterized by a pro-inflammatory transcriptional program, eventually promoting tumor growth and formation of distant metastases. We therefore hypothesize that senescence of tumor endothelial cells (TEC) represents a promising target for survival prognostication and prediction of immunotherapy efficacy in precision oncology.MethodsPublished single-cell RNA sequencing datasets of different cancer entities were analyzed for cell-specific senescence, before generating a pan-cancer endothelial senescence-related transcriptomic signature termed EC.SENESCENCE.SIG. Utilizing this signature, machine learning algorithms were employed to construct survival prognostication and immunotherapy response prediction models. Machine learning-based feature selection algorithms were applied to select key genes as prognostic biomarkers.ResultsOur analyses in published transcriptomic datasets indicate that in a variety of cancers, endothelial cells exhibit the highest cellular senescence as compared to tumor cells or other cells in the vascular compartment of malignant tumors. Based on these findings, we developed a TEC-associated, senescence-related transcriptomic signature (EC.SENESCENCE.SIG) that positively correlates with pro-tumorigenic signaling, tumor-promoting dysbalance of immune cell responses, and impaired patient survival across multiple cancer entities. Combining clinical patient data with a risk score computed from EC.SENESCENCE.SIG, a nomogram model was constructed that enhanced the accuracy of clinical survival prognostication. Towards clinical application, we identified three genes as pan-cancer biomarkers for survival probability estimation. As therapeutic perspective, a machine learning model constructed on EC.SENESCENCE.SIG provided superior pan-cancer prediction for immunotherapy response than previously published transcriptomic models.ConclusionsWe here established a pan-cancer transcriptomic signature for survival prognostication and prediction of immunotherapy response based on endothelial senescence.

Glycodelin is a potential biomarker for malignant tumors

Objective of the study to analyze and summarize the available data on the role of glycodelin in carcinogenesis and its expression in various cancers.Material and Methods. A literature search was conducted in Medline, PubMed Central, NCBI databases in the time interval from January 1983 to October 2019 using the key words glycodelin and cancer. Of the 104 publications found, 21 were used to write the review.Results. This paper presents the overview of the findings in current research focusing on the properties of glycodelin, the major lipocalin protein of the human reproductive system. Some lipocalins are known to play a key role in cancer development as well as influence signaling pathways in the regulation of cell motility, differentiation and neovascularization. Most likely they can be used as cancer markers. Glycodelin A is determined in serum and, due to its special immunoregulatory properties, can serve as a useful prognostic marker and a promising target for future anti-cancer therapies. The presence of glycodelin A in breast cancer tissue is known to be mostly linked to a better prognosis than is attributed to glycodelin-negative tissue, as glycodelin is a protein typical of differentiated tissue. On the other hand, glycodelin might play a role in neovascularisation, thereby promoting tumor growth. Glycodelin is a biomarker of aggressive malignant pleural mesothelioma and a prognostic biomarker of metastatic non-small cell lung cancer at late stages. Glycodelin hyperexpression is associated with brain metastasis in lung adenocarcinoma, and its determination can be used as an additional prognostic factor.Conclusion. The review refects basic scientifc data and results of clinical trials, as well as identifes future prospects that allow the development of new methods for cancer detection and treatment. It should be noted that glycodelin plays an important role in tumor development, progression, angiogenesis, and the formation of distant metastases, and therefore can serve as a useful diagnostic and prognostic marker. Further studies of the functional properties of glycodelin are needed to develop promising strategies in cancer therapy.

Savolitinib for non-small cell lung cancer

Savolitinib is a highly selective MET tyrosine kinase inhibitor. MET is involved in numerous cellular processes such as proliferation, differentiation and the formation of distant metastases. MET amplification and MET overexpression are quite common in many cancers, but MET exon 14 skipping alteration is most common in non-small cell lung cancer (NSCLC). The role of MET signaling as a bypass pathway in the development of acquired resistance to tyrosine kinase inhibitor (TKI) epidermal growth factor receptor (EGFR) therapy in cancer patients with EGFR gene mutation was documented. Potential beneficiaries of savolitinib therapy are patients with NSCLC and initial diagnosis of MET ex 14 skipping mutation. Savolitinib therapy can be effective in NSCLC patients with EGFR-mutant MET with progression during first-line treatment with an EGFR-TKI. Antitumor activity of savolitinib in combination with osimertinib is very promising as first-line therapy of patients with advanced EGFR-mutated NSCLC, initially with MET expression. The safety profile of savolitinib as monotherapy and in combination with osimertinib or gefitinib is so favorable in all available studies that this drug has become a very promising therapeutic option and is being intensively investigated in ongoing clinical trials.

The role of matrix metalloproteinases in pathogenesis, diagnostics, and treatment of human prostate cancer

Abstract The prostate gland is highly susceptible to oncogenic transformation, many times more than other sex tissues, such as seminal vesicles. In fact, prostate cancer (PCa) will be diagnosed in one in seven lifetime patients, making PCa the subject of intense research aimed at clarifying its biology and providing adequate treatment. PCa is the fourth most common cancer in the world in terms of the overall population and the second most common cancer for the male population. It is postulated that the development of PCa may be influenced by dietary factors, physical and sexual activity, androgens, obesity, and inflammation, but their role in the development of prostate cancer still remains unclear. Extracellular matrix metalloproteinases (MMPs) and tissue metalloproteinase inhibitors (TIMPs) play an important role in many physiological and pathological processes, including proliferation, migration, invasion, cell differentiation, participation in inflammatory processes and angiogenesis. Numerous studies point to a direct relationship between MMPs and both local tumor invasion and the formation of distant metastases. High activity of MMPs is observed in solid tumors of various origins, which positively correlates with a poor overall survival rate. Although biochemical diagnostic markers of PCa are currently available, from the point of view of clinical practice, it seems particularly important to develop new and more sensitive markers allowing for early diagnosis and long-term monitoring of patients after PCa treatment, and the assessment of MMP activity in urine and serum of patients are potential factors that could play such a role.

Neoadjuvant chemotherapy for treatment patients with rectal cancer with adverse prognostic factors: A review

Rectal cancer (RC) is one of the leading tumor location in the structure of the incidence of malignant neoplasms in the Russian Federation and the world. And the standard approach to the treatment of patients with locally advanced forms of RC is preoperative chemo-radiotherapy (CRT) with delayed surgery. The use of such sort of approach in the recent decades has led to the reduction of the frequency of local recurrence up to 10% and even less. However, approximately a third of patients die of distant metastases. In this regard, one of the main tasks in the treatment of patients with locally advanced forms of RC with adverse prognostic factors is the prevention of distant metastasis formation. Early initiation of the systemic therapy before surgery is aimed at solving this issue. Conducting neoadjuvant chemotherapy (NCT) instead of CRT in RC treatment allows to avoid radiation reactions and injuries, occurring in some patients. Two-component oxaliplatin-containing regimens are the most well studied types of NCT in the treatment of patients with non-metastatic RC. In this connection, despite the differences in the treatment regimens and the number of cycles, a good tolerability of the method as well as no effect on the frequency of postoperative complications and in general a satisfactory results comparable to the effects of CRT were observed. The use of NCT in combination with targeted treatment modalities as well as three-component chemotherapy regimens are promising and encouraging treatment options for patients with RC with adverse prognostic factors.

Proliferative activity of cancer stem cells in the prognosis of hematogenous metastasis of colon adenocarcinoma

The search for prognostic markers to determine the risk of dissemination and metastasis of colon adenocarcinoma is one of the most difficult and actual problems of modern oncomorphology.The aim of this work was to determine the possibility of using indicators of the proliferative activity of cancer stem cells in the prediction of hematogenous metastasis of colon adenocarcinoma. In this work the surgical material from 32 radically operated patients of different ages suffering from a localized colon adenocarcinoma was explored, and relapse-free survival was assessed. A comparative analysis of various components of the tumor differon, including proliferating stem cells and their relationship with the formation of relapse was carried out.An index of stem cell proliferation was proposed to assess the influence of stem cell activity on the biological behavior of tumor. The best rates of relapse-free survival were found in the group of patients with low value of the index of stem cell proliferation compared with patients which index took on high values, which is more typical for elderly and old patients. With a similar comparison of other indicators of tumor differon, including the percentage of ALDH1 and Ki-67-positive cells, as well as cells with the ALDH1+Ki-67+immenophenotype relative to the total tumor differon, no significant relationship with relapse-free survival was found. These results may indicate a high role of ALDH1+ cell proliferation in tumor dissemination, especially in elderly and senile patients, and a lesser influence of both the proliferative activity of Ki-67 and the general population of stem cells on the formation of distant metastases.

The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.

Simple SummaryMitochondria are essential cellular organelles, involved in controlling energy production, cell metabolism, cell growth, and cell death. Since cellular functions are de-regulated in cancer, it is not surprising that mitochondria dysfunctions have been observed in this disease. One key aspect in controlling tumor formation and progression is the interaction between the cancer cells and their surrounding environment, known as the tumor microenvironment. The extracellular matrix is an abundant component of the tumor microenvironment and it has been shown to affect tumor initiation and progression. Here, we will explore how the interaction between cancer cells and the extracellular matrix impinges on mitochondria function during cancer progression.The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis—these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis.