Colorectal cancer and dormant metastases: Put to sleep or destroy?

After reading the review by An et al "Biological factors driving colorectal cancer metastasis", which covers the problem of the metastasis of colorectal cancer (CRC), I had a desire to discuss with readers one of the exciting problems associated with dormant metastases. Most deaths from CRCs are caused by metastases, which can be detected both at diagnosis of the primary tumor and several years or even decades after treatment. This is because tumor cells that enter the bloodstream can be destroyed by the immune system, cause metastatic growth, or remain dormant for a long time. Dormant tumor cells may not manifest themselves throughout a person's life or, after some time and under appropriate conditions, may give rise to the growth of metastases. In this editorial, we will discuss the most important features of dormant metastases and the mechanisms of premetastatic niche formation, as well as factors that contribute to the activation of dormant metastases in CRCs. We will pay special attention to the possible mechanisms involved in the formation of circulating tumor cell complexes and the choice of therapeutic strategies that promote the dormancy or destruction of tumor cells in CRCs.

Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance.

BACKGROUND: Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. AIM: To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). METHODS: A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. RESULTS: Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). CONCLUSION: The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.

Predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa squamous cell lung cancer: A retrospective analysis.

BACKGROUND: Lung cancer (LC) is a global medical, social and economic problem and is one of the most common cancers and the leading cause of mortality from malignant neoplasms. LC is characterized by an aggressive course, and in the presence of disease recurrence risk factors, patients, even at an early stage, may be indicated for adjuvant therapy to improve survival. However, combined treatment does not always guarantee a favorable prognosis. In this regard, establishing predictors of LC recurrence is highly important both for determining the optimal treatment plan for the patients and for evaluating its effectiveness. AIM: To establish predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa lung squamous cell carcinoma (LSCC). METHODS: A retrospective case-control cohort study included 69 patients with LSCC who underwent radical surgery at the Orenburg Regional Clinical Oncology Center from 2009 to 2018. Postoperatively, all patients received adjuvant chemotherapy. Histological samples of the resected lung were stained with Mayer's hematoxylin and eosin and examined under a light microscope. Univariate and multivariate analyses were used to identify predictors associated with the risk of disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with a high risk of disease recurrence and those with a low risk of disease recurrence. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. Differences were considered to be significant at P < 0.05. RESULTS: The following predictors of a high risk of disease recurrence in patients with stage IIb-IIa LSCC were established: a low degree of tumor differentiation [odds ratio (OR) = 7.94, 95%CI = 1.08-135.81, P = 0.049]; metastases in regional lymph nodes (OR = 5.67, 95%CI = 1.09-36.54, P = 0.048); the presence of loose, fine-fiber connective tissue in the tumor stroma (OR = 21.70, 95%CI = 4.27-110.38, P = 0.0002); and fragmentation of the tumor solid component (OR = 2.53, 95%CI = 1.01-12.23, P = 0.049). The area under the curve of the predictive model was 0.846 (95%CI = 0.73-0.96, P < 0.0001). The sensitivity, accuracy and specificity of the method were 91.8%, 86.9% and 75.0%, respectively. In the group of patients with a low risk of LSCC recurrence, the 1-, 2- and 5-year disease-free survival (DFS) rates were 84.2%, 84.2% and 75.8%, respectively, while in the group with a high risk of LSCC recurrence the DFS rates were 71.7%, 40.1% and 8.2%, respectively (P < 0.00001). Accordingly, in the first group of patients, the 1-, 2- and 5-year overall survival (OS) rates were 94.7%, 82.5% and 82.5%, respectively, while in the second group of patients, the OS rates were 89.8%, 80.1% and 10.3%, respectively (P < 0.00001). CONCLUSION: The developed method allows us to identify a group of patients at high risk of disease recurrence and to adjust to ongoing treatment.

Genetic heterogeneity of colorectal cancer and the microbiome.

In 2020, the International Agency for Research on Cancer and the World Health Organization's GLOBOCAN database ranked colorectal cancer (CRC) as the third most common cancer in the world. Most cases of CRC (> 95%) are sporadic and develop from colorectal polyps that can progress to intramucosal carcinoma and CRC. Increasing evidence is accumulating that the gut microbiota can play a key role in the initiation and progression of CRC, as well as in the treatment of CRC, acting as an important metabolic and immunological regulator. Factors that may determine the microbiota role in CRC carcinogenesis include inflammation, changes in intestinal stem cell function, impact of bacterial metabolites on gut mucosa, accumulation of genetic mutations and other factors. In this review, I discuss the major mechanisms of the development of sporadic CRC, provide detailed characteristics of the bacteria that are most often associated with CRC, and analyze the role of the microbiome and microbial metabolites in inflammation initiation, activation of proliferative activity in intestinal epithelial and stem cells, and the development of genetic and epigenetic changes in CRC. I consider long-term studies in this direction to be very important, as they open up new opportunities for the treatment and prevention of CRC.

Microbiota of the gastrointestinal tract: Friend or foe?

The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.

Helicobacter Pylori and Gastric Cancer Progression.

Gastric cancer (GC) remains the fifth most common malignant tumor and the third leading cause of cancer death, despite the decline in incidence and mortality worldwide over the past five decades. Currently, the roles of Helicobacter pylori (H. pylori) in the development of GC have been established. The effects of H. pylori are mediated through interactions of H. pylori pathogen-associated molecular patterns (PAMPs) with pattern-recognition receptors (PRRs) located on immune and epithelial cells. It is known that this interaction leads to the generation of reactive oxygen species (ROS), activation of the mechanisms of angiogenesis, epithelial-mesenchymal transformation (EMT), and immunological tolerance. Not all this excludes the possibility that H. pylori may have an effect not only on the induction, but also on the mechanisms of GC progression. In this review, we will consider the main structural elements of the innate immune system and the mechanisms of their interaction with H. pylori; the possible role of H. pylori in GC progression; relationship of H. pylori with clinical and pathological characteristics and prognosis of GC, as well as data on the effect of eradication therapy on long-term results of GC patient treatment.

Helicobacter pylori in gastric cancer: Features of infection and their correlations with long-term results of treatment.

BACKGROUND: Helicobacter pylori (H. pylori) is a spiral-shaped bacterium responsible for the development of chronic gastritis, gastric ulcer, gastric cancer (GC), and MALT-lymphoma of the stomach. H. pylori can be present in the gastric mucosa (GM) in both spiral and coccoid forms. However, it is not known whether the severity of GM contamination by various vegetative forms of H. pylori is associated with clinical and morphological characteristics and long-term results of GC treatment. AIM: To establish the features of H. pylori infection in patients with GC and their correlations with clinical and morphological characteristics of diseases and long-term results of treatment. METHODS: Of 109 patients with GC were included in a prospective cohort study. H. pylori in the GM and tumor was determined by rapid urease test and by immunohistochemically using the antibody to H. pylori. The results obtained were compared with the clinical and morphological characteristics and prognosis of GC. Statistical analysis was performed using the Statistica 10.0 software. RESULTS: H. pylori was detected in the adjacent to the tumor GM in 84.5% of cases, of which a high degree of contamination was noted in 50.4% of the samples. Coccoid forms of H. pylori were detected in 93.4% of infected patients, and only coccoid-in 68.9%. It was found that a high degree of GM contamination by the coccoid forms of H. pylori was observed significantly more often in diffuse type of GC (P = 0.024), in poorly differentiated GC (P = 0.011), in stage T3-4 (P = 0.04) and in N1 (P = 0.011). In cases of moderate and marked concentrations of H. pylori in GM, a decrease in 10-year relapse free and overall survival from 55.6% to 26.3% was observed (P = 0.02 and P = 0.07, respectively). The relationship between the severity of the GM contamination by the spiral-shaped forms of H. pylori and the clinical and morphological characteristics and prognosis of GC was not revealed. CONCLUSION: The data obtained indicates that H. pylori may be associated not only with induction but also with the progression of GC.

Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer.

Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.

Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer.

The determination of factors associated with progression of cervical cancer is important, both for a recurrence risk assessment and for determining optimal treatment tactics. Previously, we showed the prognostic value of different types of tumor microvessels (MVs) in gastric and breast cancer. The object of this research was to study the morphology and clinical significance of different tumor microvessels in early cervical cancer. A total of 65 archived paraffin blocks of patients with I-IIA stages of squamous cervical cancer were investigated. Samples were stained with Mayer hematoxylin and immunohistochemically using antibodies to CD34, podoplanin, HIF-1a, and Snail. The eight types of tumor MVs differed in morphology were identified. It was established that only the dilated capillaries (DСs) with weak expression of CD34, the contact type DCs, the capillaries in tumor solid component, and the lymphatic vessels in the lymphoid and polymorphic cell infiltrates of tumor stroma are associated with clinical and pathological characteristics of early cervical cancer. Preliminary results also suggest that a combination of fragmentation in tumor solid component and the contact type DCs may predict a recurrence of early cervical cancer. Given the small number of cervical cancer recurrences, the predictive significance of the described markers requires a more thorough examination.

Different types of tumor vessels in breast cancer: morphology and clinical value.

Angiogenesis is a key factor of tumor progression. Considering, that the tumor vessels are heterogeneous and differ in morphology and clinical significance, the purpose of this research was to study of the morphological features of tumor vessels and their relationship with the clinical characteristics and morphological features of breast cancer (BC). In this pilot study the tumor samples received from 59 patients with T1-T2 stages of ductal invasive carcinomas were included. The sections were stained with hematoxylin and eosin and immunohistochemically using antibodies to CD34. The morphological features and the number of different types of tumor vessels were assessed microscopically and were compared with grade, lymph node metastasis, hormone receptors, HER2/neu status and with the presence of tumor emboli in vessels (lymphovascular invasion). We identified the following types of tumor vessels in BC: the normal microvessels, the dilated capillaries of peritumoral stroma, the atypical dilated capillaries and the "cavitary" structures (CS) type-1 and type-2 relating to the "cavitary" type of angiogenesis that was described by us earlier. The number of dilated capillaries correlated with CS type-1 (p = 0.003), CS type-2 (p = 0.002), atypical dilated capillaries (p = 0.0008) and with lymphovascular invasion (p = 0.005); the presence of atypical dilated capillaries-with CS type-1 (p < 0.00001), CS type-2 (p = 0.00004), lymphovascular invasion (p = 0.0002) and with the tumor grade (p = 0.003); the number of CS type-1-with estrogen receptor (p = 0.002) and progesterone receptor (p = 0.002) status and with lymphovascular invasion (p = 0.004); the presence of CS type-2-with positive Her2/new status (p = 0.0002) and lymphovascular invasion (p = 0.01). The density of normal microvessels was not associated with other types of tumor vessels and with clinical characteristics of BC. These data indicate that varied types of tumor vessels are associated with different morphological characteristics of BC, such as hormone receptors and HER2/neu status, lymphovascular invasion. We believe that the atypical dilated capillaries are related to the "cavitary" type of angiogenesis. The strong correlations of lymphovascular invasion with CS type-1 and atypical dilated capillaries testify that the "cavitary" type of angiogenesis may play a significant role in the formation of tumor emboli in the vessels.