Double Recombinant Vaccinia Virus: A Candidate Drug against Human Glioblastoma

Glioblastoma is one of the most aggressive brain tumors. Given the poor prognosis of this disease, novel methods for glioblastoma treatment are needed. Virotherapy is one of the most actively developed approaches for cancer therapy today. VV-GMCSF-Lact is a recombinant vaccinia virus with deletions of the viral thymidine kinase and growth factor genes and insertions of the granulocyte–macrophage colony-stimulating factor and oncotoxic protein lactaptin genes. The virus has high cytotoxic activity against human cancer cells of various histogenesis and antitumor efficacy against breast cancer. In this work, we show VV-GMCSF-Lact to be a promising therapeutic agent for glioblastoma treatment. VV-GMCSF-Lact effectively decreases the viability of glioblastoma cells of both immortalized and patient-derived cultures in vitro, crosses the blood–brain barrier, selectively replicates into orthotopically transplanted human glioblastoma when intravenously injected, and inhibits glioblastoma xenograft and metastasis growth when injected intratumorally.

Metastasis Initiation Precedes Detection of Primary Cancer—Analysis of Metastasis Growth in vivo in a Colorectal Cancer Test Case

Most cases of deaths from colorectal cancer (CRC) result from metastases, which are often still undetectable at disease detection time. Even so, in many cases, shedding is assumed to have taken place before that time. The dynamics of metastasis formation and growth are not well-established. This work aims to explore CRC lung metastasis growth rate and dynamics. We analyzed a test case of a metastatic CRC patient with four lung metastases, with data of four serial computed tomography (CT) scans measuring metastasis sizes while untreated. We fitted three mathematical growth models—exponential, logistic, and Gompertzian—to the CT measurements. For each metastasis, a best-fitted model was determined, tumor doubling time (TDT) was assessed, and metastasis inception time was extrapolated. Three of the metastases showed exponential growth, while the fourth showed logistic restraint of the growth. TDT was around 93 days. Predicted metastasis inception time was at least 4–5 years before the primary tumor diagnosis date, though they did not reach detectable sizes until at least 1 year after primary tumor resection. Our results support the exponential growth approximation for most of the metastases, at least for the clinically observed time period. Our analysis shows that metastases can be initiated before the primary tumor is detectable and implies that surgeries accelerate metastasis growth.

Linear mixed-effects models for estimation of pulmonary metastasis growth rate: implications for CT surveillance in patients with sarcoma

Objectives: Sarcoma patients often undergo surveillance chest CT for detection of pulmonary metastases. No data exist on the optimal surveillance interval for chest CT. The aim of this study was to estimate pulmonary metastasis growth rate in sarcoma patients. Methods: This was a retrospective review of 95 patients with pulmonary metastases (43 patients with histologically confirmed metastases and 52 with clinically diagnosed metastases) from sarcoma treated at an academic tertiary-care center between 01 January 2000 and 01 June 2019. Age, sex, primary tumor size, grade, subtype, size and volume of the pulmonary metastasis over successive chest CT scans were recorded. Two metastases per patient were chosen if possible. Multivariate linear mixed-effects models with random effects for each pulmonary metastasis and each patient were used to estimate pulmonary metastasis growth rate, evaluating the impact of patient age, tumor size, tumor grade, chemotherapy and tumor subtype. We estimated the pulmonary metastasis volume doubling time using these analyses. Results: Maximal primary tumor size at diagnosis (LRT statistic = 2.58, df = 2, p = 0.275), tumor grade (LRT statistic = 1.13, df = 2, p = 0.567), tumor type (LRT statistic = 7.59, df = 6, p = 0.269), and patient age at diagnosis (LRT statistic = 0.735, df = 2, p = 0.736) were not statistically significant predictors of pulmonary nodule growth from baseline values. Chemotherapy decreased the rate of pulmonary nodule growth from baseline (LRT statistic = 7.96, df = 2, p = 0.0187). 95% of untreated pulmonary metastases are expected to grow less than 6 mm in 6.4 months. There was significant intrapatient and interpatient variation in pulmonary metastasis growth rate. Pulmonary metastasis volume growth rate was best fit with an exponential model in time. The volume doubling time for pulmonary metastases assuming an exponential model in time was 143 days (95% CI (104, 231) days). Conclusions: Assuming a 2 mm nodule is the smallest reliably detectable nodule by CT, the data suggest that an untreated pulmonary metastasis is expected to grow to 8 mm in 8.4 months (95% CI (4.9, 10.2) months). Tumor size, grade and sarcoma subtype did not significantly alter pulmonary metastasis growth rate. However, chemotherapy slowed the pulmonary metastasis growth rate. Advances in knowledge: CT surveillance intervals for pulmonary metastases can be estimated based on metastasis growth rate. There was significant variation in the pulmonary metastasis growth rate between metastases within patient and between patients. Pulmonary nodule volume growth followed an exponential model, linear in time.

Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth

Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C+CCR2+ inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis–associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.

Studying Bone Remodelling and Tumour Growth for Therapy Predictive Control

Bone remodelling consists of cycles of bone resorption and formation executed mainly by osteoclasts and osteoblasts. Healthy bone remodelling is disrupted by diseases such as Multiple Myeloma and bone metastatic diseases. In this paper, a simple mathematical model with differential equations, which takes into account the evolution of osteoclasts, osteoblasts, bone mass and bone metastasis growth, is improved with a pharmacokinetic and pharmacodynamic (PK/PD) scheme of the drugs denosumab, bisphosphonates, proteasome inhibitors and paclitaxel. The major novelty is the inclusion of drug resistance phenomena, which resulted in two variations of the model, corresponding to different paradigms of the origin and development of the tumourous cell resistance condition. These models are then used as basis for an optimization of the drug dose applied, paving the way for personalized medicine. A Nonlinear Model Predictive Control scheme is used, which takes advantage of the convenient properties of a suggested adaptive and democratic variant of Particle Swarm Optimization. Drug prescriptions obtained in this way provide useful insights into dose administration strategies. They also show how results may change depending on which of the two very different paradigms of drug resistance is used to model the behaviour of the tumour.

Clinicopathological and prognostic significance and molecular mechanisms governing uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Although UM and cutaneous melanoma are derived from melanocytes, UM differs clinically and biologically from its more common skin counterparts. More than half of primary UMs metastasize. However, there is currently no effective treatment for metastatic UM. Therefore, studying mutations related to the metastasis, growth, proliferation, and survival of UM can help researchers understand its pathogenesis and metastatic mechanism, thereby leading to a more effective treatment. In addition, we provide an overview of the recent basic and clinical studies to provide a strong foundation for developing novel anti-carcinogenesis targets for future interventions.

Difficulties associated with differential diagnosis between brain metastases and foci of necrosis resulted from stereotactic radiotherapy (case report and literature review)

Modern advances in oncology can achieve significantly better results in terms of life expectancy in patients with metastatic brain disease. The combination of surgery, systemic therapy, whole brain irradiation and local methods of radiation therapy lead to good indicators for controlling the manifestations of the disease in the brain. Of course, intensification of treatment increases the risk of iatrogenic complications. The use of aggressive stereotactic radiotherapy regimens leads not only to high local control of irradiated metastases, but also to the risk of so-called radiation necrosis. The use of the most up-to-date diagnostic methods does not always allow one to unequivocally differentiate radiation necrosis from continued metastasis growth. The above example shows the need for a careful assessment of such situations and a multidisciplinary approach to interpreting the results of stereotactic radiotherapy.

Consecutive seeding and transfer of genetic diversity in metastasis

During metastasis, only a fraction of genetic diversity in a primary tumor is passed on to metastases. We calculate this fraction of transferred diversity as a function of the seeding rate between tumors. At one extreme, if a metastasis is seeded by a single cell, then it inherits only the somatic mutations present in the founding cell, so that none of the diversity in the primary tumor is transmitted to the metastasis. In contrast, if a metastasis is seeded by multiple cells, then some genetic diversity in the primary tumor can be transmitted. We study a multitype branching process of metastasis growth that originates from a single cell but over time receives additional cells. We derive a surprisingly simple formula that relates the expected diversity of a metastasis to the diversity in the pool of seeding cells. We calculate the probability that a metastasis is polyclonal. We apply our framework to published datasets for which polyclonality has been previously reported, analyzing 68 ovarian cancer samples, 31 breast cancer samples, and 8 colorectal cancer samples from 15 patients. For these clonally diverse metastases, under typical metastasis growth conditions, we find that 10 to 150 cells seeded each metastasis and left surviving lineages between initial formation and clinical detection.

Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition

Hepatic metastatic growth is dependent upon stromal factors including the matrisomal proteins that make up the extracellular matrix (ECM). Laminins are ECM glycoproteins with several functions relevant to tumour progression including angiogenesis. We investigated whether metastatic colon cancer cells produce the laminins required for vascular basement membrane assembly as a mechanism for the promotion of angiogenesis and liver metastasis growth. qPCR was performed using human-specific primers to laminin chains on RNA from orthotopic human colorectal liver metastases. Laminin α5 (LAMA5) expression was inhibited in colon cancer cells using shRNA. Notch pathway gene expression was determined in endothelia from hepatic metastases. Orthotopic hepatic metastases expressed human laminin chains α5, β1 and γ1 (laminin 511), all of which are required for vascular basement membrane assembly. The expression of Laminin 511 was associated with reduced survival in several independent colorectal cancer cohorts and angiogenesis signatures or vessel density significantly correlated with LAMA5 expression. Colorectal cancer cells in culture made little LAMA5, but its levels were increased by culture in a medium conditioned by tumour-derived CD11b+ myeloid cells through TNFα/NFκB pathway signalling. Down-regulation of LAMA5 in cancer cells impaired liver metastatic growth and resulted in reduced intra-tumoural vessel branching and increased the expression of Notch pathway genes in metastasis-derived endothelia. This data demonstrates a mechanism whereby tumour inflammation induces LAMA5 expression in colorectal cancer cells. LAMA5 is required for the successful growth of hepatic metastases where it promotes branching angiogenesis and modulates Notch signalling.