Breast cancer brain metastases (BrM) are a common and fatal complication in advanced breast cancer patients, with the intricate brain microenvironment significantly limiting the efficacy of current therapeutic strategies. Recently, the neuro-astrocytic network, as a core component of the brain metastasis microenvironment, has garnered extensive attention for its pivotal role in supporting tumor adaptive growth. This review systematically outlines the adaptive mechanisms of the neuro-astrocytic network in BrM, including bidirectional interactions between tumor cells, neurons, and astrocytes, and their profound effects on synapse-like signaling, metabolic pathways, and regulatory networks. Furthermore, we integrate recent advancements in exploring therapeutic targets and discuss potential intervention strategies against tumor-microenvironment interactions and associated challenges. Future research focusing on the multi-target collaborative mechanisms within this network and its clinical translational potential may provide new avenues for precise treatment of BrM.

Colorectal cancer liver metastasis (CRLM) is a leading cause of death in colorectal cancer (CRC) patients and is characterized by an immunosuppressive tumor microenvironment (TME). This study employs mouse in vivo selection to isolate highly metastatic CRLM derivatives for profiling their transcriptomic, proteomic, and metabolomic alterations associated with CRLM. Notably, the expression of SLAMF3 is significantly upregulated in CRLM derivatives and its knockdown effectively suppresses CRLM in mice. RUNX1 transcriptionally upregulates SLAMF3 expression and combined targeting of the RUNX1/SLAMF3 axis synergistically suppresses liver metastasis in mice. In parallel, SLAMF3 suppresses macrophage-mediated phagocytosis of CRC cells through the SHP-1/2/mTORC1 pathway. Conversely, SLAMF3 knockdown promotes M1 polarization in liver metastases and activates the CCL signaling pathway between macrophages and CD8+ T cells. It also reduces the exhausted CD8+ T cells in liver metastases and the expression of inhibitory receptors PD-1 and TIM-3, thus alleviating the immunosuppressive TME. Clinically, activation of the RUNX1/SLAMF3 axis is closely associated with CRLM progression and correlates with a reduced proportion of clinically beneficial C1QC⁺ tumor-associated macrophages (TAMs). Collectively, these findings identify the RUNX1/SLAMF3 axis as a key driver of immunosuppressive TME remodeling and CRLM progression, highlighting its potential as a promising therapeutic target for CRLM.

While primary breast cancer (BC) is often effectively managed, metastasis remains the primary cause of BC-related fatalities. Gaps remain in our understanding of the mechanisms regulating cancer cell organotropism with predilection to specific organs. Unraveling mediators of site-specific metastasis could enhance early detection and enable more tailored interventions. Liquid biopsy represents an innovative approach in cancer involving the analysis of biological materials such as circulating tumor DNA and tumor-derived extracellular vesicles (EV) found in body fluids like blood or urine. This offers valuable insights for characterizing and monitoring tumor genomes to advance personalized medicine in metastatic cancers.

We performed in-depth analyses of EV cargo associated with BC metastasis using eight murine cell line models with distinct metastatic potentials and organotropism to the lung, the bone, the liver, and the brain. We characterized the secretome of these cells to identify unique biomarkers specific to metastatic sites.

Small EVs isolated from all cell lines were quantified and validated for established EV markers. Tracking analysis and electron microscopy revealed EV secretion patterns that differed according to cell line. Cell-free (cf)DNA and EV-associated DNA (EV-DNA) were detected from all cell lines with varying concentrations. We detected a TP53 mutation in both EV-DNA and cfDNA. Mass spectrometry-based proteomics analyses identified 698 EV-associated proteins, which clustered according to metastatic site. This analysis highlighted both common EV signatures and proteins involved in cancer progression and organotropism unique to metastatic cell lines. Among these, 327 significantly differentially enriched proteins were quantified with high confidence levels across BC and metastatic BC cells. We found enrichment of specific integrin receptors in metastatic cancer EVs compared to EVs secreted from non-transformed epithelial cells and matched tumorigenic non-metastatic cells. Pathway analyses revealed that EVs derived from parental cancer cells display a cell adhesion signature and are enriched with proteins involved in cancer signaling pathways.

Taken together, the characterization of EV cargo in a unique model of BC organotropism demonstrated that EV-DNA and EV proteomes were informative of normal and cancer states. This work could help to identify BC biomarkers associated with site-specific metastasis and new therapeutic targets.

Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and bone resorption, in osteolytic conditions such as osteoporosis and bone metastases. However, its role in metastasis progression remains incompletely understood. Herein, we examined whether the overexpression of human RANKL in transgenic mice (TgRANKL) affects their susceptibility to breast cancer bone metastasis compared to their wild-type (WT) littermates. Bone metastasis was induced by injecting EO771 mouse mammary adenocarcinoma cells into the caudal artery of syngeneic WT and TgRANKL mice. RANKL overexpression led to an earlier onset and increased burden of bone metastasis in EO771-bearing TgRANKL mice compared to WT mice. It also exacerbated the bone destruction caused by metastasis-associated osteolysis. The prophylactic inhibition of RANKL activity with denosumab, a monoclonal antibody targeting human RANKL, prevented osteolysis and significantly reduced the incidence and progression of bone metastases in TgRANKL mice. However, the therapeutic denosumab treatment had no effect on metastasis incidence or tumor burden, although it alleviated osteolysis. The treatment with zoledronic acid, an anti-resorptive agent inhibiting osteoclast activity, yielded results similar to those of denosumab. These findings emphasize the significance of initiating early treatment with anti-resorptive agents such as denosumab or zoledronic acid to reduce the risk of bone metastasis in patients at high risk.

Microwave dynamic therapy (MDT) is promising in tumor therapy by generation of toxic reactive oxygen species (ROS), whose therapeutic efficacy is severely compromised by hypoxia and the antioxidant defense in the tumor microenvironment (TME). To address these bottlenecks, we designed a multifunctional nanoregulator CoMnMOF@Apatinib@l-menthol@RBC-HA (denoted as CMALRH) to achieve enhanced MDT via a multi-pronged ROS amplification strategy. We demonstrated that the enhanced ROS generation is attributed to the up-regulate O2 level, down-regulate vascular endothelial growth factor (VEGF) expression and deplete glutathione (GSH). Meanwhile, CMALRH is verified to perform superior microwave (MW) thermal effect, thus remarkably potentiating the efficacy of anti-tumor therapy. The experiments in vitro and in vivo confirmed the enhanced MDT in combination with microwave thermal therapy can successfully inhibit the proliferation of breast cancer. This TME based ROS amplification strategy provides an avenue for the development of remarkably high efficiency MDT and MW thermal therapy.

Lung carcinoma (LC) is the primary cause of millions of deaths worldwide. As LC is typically diagnosed at a later stage, its prevention and treatment are difficult. The pathological basis of both types of LC, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), is highly determined. The only treatments available for LC are surgical resection and chemotherapy, which require sophisticated new treatments. Biomarkers are promising treatment options, because they can be used for both diagnosis and treatment. Typical signaling molecules known as biomarkers identify abnormalities in cellular activity and serve as prognostic and diagnostic indicators. Biomarkers show great promise in clinical decision making, early and quick diagnosis, recurrence of illness, and tracking the effectiveness of cancer treatments. This review provides an overview of biomarkers, their benefits, and future directions for those new to the field of biomarker research in LC therapy.

Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapies. It also considers when would be the optimal time to employ this type of therapy.

Circulating tumor cells (CTCs) are important biomarkers for cancer diagnosis and treatment monitoring. However, their scarcity limits their utility as current enrichment techniques are hampered by low volume throughput and/or the inability to capture CTCs with low target antigen densities. Our group previously reported a device capable of processing samples in a flow manner using an optimized Halbach array to enhance the capture of low EpCAM-expressing cells (Flow-through Immunomagnetic CTC Enrichment system). In this study, we tested the capture efficiency of eight commercially available streptavidin magnetic beads using this device to identify the most suitable bead. Results indicate that using this system, the best-performing magnetic beads are in the ~ 100 to ~ 150 nm size range. Considering the combination of binding efficiency and final sample purity, we found that among the beads tested in combination with biotinylated anti-EpCAM, MojoSort Streptavidin Nanobeads performed the best, with high capture efficiencies for both the high EpCAM expressing LNCaP and low EpCAM expressing PC3-9 cell lines. For CTC enrichment from the blood of cancer patients, reducing the number of WBCs co-enriched with these beads will be essential, especially when processing large-volume samples acquired, for instance, through diagnostic leukapheresis to overcome the limitations caused by the scarcity of CTCs.

Oñate and colleagues demonstrate that KITL expression in pancreatic stellate cells is crucial for maintaining the inherent tumor-suppressive function of the pancreatic microenvironment, and its loss enables pancreatic cancer development. This pivotal discovery not only reinforces the century-old hypothesis of natural microenvironmental tumor suppression but also highlights a promising therapeutic avenue whereby restoring KITL expression could reestablish the tumor-suppressive functions of pancreas-resident fibroblastic cells. See related article by Oñate et al., p. 913.

Herein, we present the case of a 73-year-old man with recurrent pancreatic tumors 20 years postnephrectomy for clear cell renal cell carcinoma (RCC). Imaging studies revealed multiple hypervascular tumors in the pancreas, posing a diagnostic challenge in differentiating RCC metastases from well-differentiated neuroendocrine tumors (NETs). Magnetic resonance imaging (MRI) chemical shift imaging played a pivotal role in suggesting the presence of fat, supporting RCC metastasis. Surgical resection confirmed the diagnosis.

Renal cell carcinoma (RCC) is among the most frequently occurring types of cancer, and its metastasis is a major contributor to its elevated mortality. Before the primary tumor metastasizes to secondary or distant organs, it remodels the microenvironment of these sites, creating a pre-metastatic niche (PMN) conducive to the colonization and growth of metastatic tumors. RCC releases a variety of biomolecules that induce angiogenesis, alter vascular permeability, modulate immune cells to create an immunosuppressive microenvironment, affect extracellular matrix remodeling and metabolic reprogramming, and determine the organotropism of metastasis through different signaling pathways. This review summarizes the principal processes and mechanisms underlying the formation of the premetastatic niche in RCC. Additionally, we emphasize the significance and potential of targeting PMNs for the prevention and treatment of tumor metastasis in future therapeutic approaches. Finally, we summarized the currently potential targeted strategies for detecting and treating PMN in RCC and provide a roadmap for further in-depth studies on PMN in RCC.

Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.

The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness - a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.

Breast cancer is the primary cause of cancer-related death and the most frequent malignancy among women in Western countries. Although there have been advancements in combination treatments and targeted therapies for the metastatic diseases management, metastatic breast cancer is still the second most common cause of cancer-related deaths among U.S. women. The routes of metastasis encompass invasion, intravasation, circulation, extravasation, infiltration into a remote location to establish a metastatic niche, and the formation of micro-metastases in a new environment. Each of these processes is regulated by changes in gene expression. MicroRNAs (miRNAs) are widely expressed by a variety of organisms and have a key role in cell activities including suppressing or promoting cancer through regulating various pathways. Target gene expression is post-transcriptionally regulated by miRNAs, which contribute to the development, spread, and metastasis of breast cancer. In this study, we comprehensively discussed the role of miRNAs as predictors of breast cancer metastasis, their correlation with the spread of the disease to certain organs, and their potential application as targets for breast cancer treatment. We also provided molecular mechanisms of miRNAs in the progression of breast cancer, as well as current challenges in miRNA-based therapeutic approaches. Furthermore, as one of the primary issues with the treatment of solid malignancies is the efficient delivery of miRNAs, we examined a number of cutting-edge carriers for miRNA-based therapies and CRISPR/Cas9 as a targeted therapy for breast cancer.

Metastatic cancer is reported to have a mortality rate of 90%. Understanding the underlying principles of metastasis and quantifying them through mathematical modelling provides insights into potential treatment regimes. This work presents a partial differential equation based mathematical model embedded on a network, representing the organs and the blood vessels between them, with the aim of predicting likely secondary metastatic sites. Through this framework the relationship between metastasis and blood flow and between metastasis and the diffusive behaviour of cancer is explored. An analysis of the model predictions showed a good correlation with clinical data for some cancer types, particularly for cancers originating in the gut and liver. The model also predicts an inverse relationship between blood velocity and the concentration of cancer cells in secondary organs. Finally, for anisotropic diffusive behaviour, where the cancer experiences greater diffusivity in one direction, metastatic efficiency decreased. This is aligned with the clinical observation that gliomas of the brain, which typically show anisotropic diffusive behaviour, exhibit fewer metastases. The investigation yields some valuable results for clinical practitioners and researchers-as it clarifies some aspects of cancer that have hitherto been difficult to study, such as the impact of differing diffusive behaviours and blood flow rates on the global spread of cancer. The model provides a good framework for studying cancer progression using cancer-specific information when simulating metastasis.

Colorectal carcinoma (CRC) exhibits metastatic organotropism, primarily targeting liver, lung, and rarely the brain. Here, we study chromosomal imbalances (CIs) in cohorts of primary CRCs and metastases. Brain metastases show the highest burden of CIs, including aneuploidies and focal CIs, with enrichment of +12p encoding KRAS. Compared to liver and lung metastases, brain metastases present with increased co-occurrence of KRAS mutation and amplification. CRCs with concurrent KRAS mutation and amplification display significant metabolic reprogramming with upregulation of glycolysis, alongside upregulation of cell cycle pathways, including copy number gains of MDM2 and CDK4. Evolutionary modeling suggests early acquisition of many organotropic CIs enriched in both liver and brain metastases, while brain-enriched CIs preferentially emerge later. Collectively, this study supports a model where cytogenetic events in CRCs favor site-specific metastatic colonization. These site-enriched CI patterns may serve as biomarkers for metastatic potential in precision oncology.

The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.

Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.

The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains one of the leading causes of cancer-related mortality worldwide. The high mortality rate is primarily driven by delayed diagnosis, rapid metastasis, and frequent recurrence. Tumor-derived exosomes (TEXs) have emerged as critical mediators in NSCLC progression, offering valuable insights into the tumor microenvironment. Exosomes are small membrane vesicles that facilitate intercellular communication and transport bioactive molecules, including proteins, RNAs, and DNAs, thereby reflecting the genetic complexity of tumors. These exosomes play a key role in promoting tumor metastasis, epithelial-mesenchymal transition (EMT), neovascularization, drug resistance, and immune evasion, all of which are pivotal in the development of NSCLC. This review explores the diverse roles of TEXs in NSCLC progression, focusing on their involvement in pre-metastatic niche formation, tissue metastasis, and immune modulation. Specifically, we discuss the roles of exosome-associated RNAs and proteins in NSCLC, and their contribute to tumor growth and metastasis. Furthermore, we explore the potential of TEXs as biomarkers for NSCLC, emphasizing their application in diagnosis, prognosis, and prediction of resistance to targeted therapies and immunotherapies.

Brain metastases are the most commonly diagnosed type of central nervous system tumor, yet the mechanisms of their occurrence are still widely unknown. Lung cancer, breast cancer, and melanoma are the most common etiologies, but renal and colorectal cancers have also been described as metastasizing to the brain. Regardless of their origin, there are common mechanisms for progression to all types of brain metastases, such as the creation of a suitable tumor microenvironment in the brain, priming of tumor cells, adaptations to survive spreading in lymphatic and blood vessels, and development of mechanisms to penetrate the blood-brain barrier. However, there are complex genetic and molecular interactions that are specific to every type of primary tumor, making the understanding of the metastatic progression of tumors to the brain a challenging field of study. In this review, we aim to summarize current knowledge on the pathophysiology of brain metastases, from specific genetic characteristics of commonly metastatic tumors to the molecular and cellular mechanisms involved in progression to the central nervous system. We also briefly discuss current challenges in targeted therapies for brain metastases and how there is still a gap in knowledge that needs to be overcome to improve patient outcomes.

Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.

Pre-metastatic niche (PMN) formation is essential for metastatic development and drives organotropism. Tumour-derived extracellular vesicles and soluble factors remodel the microenvironment of distant metastatic organs before subsequent metastasis. Dogs with osteosarcoma (OS) have proven to be excellent disease models for their human companions. Here, we show evidence of PMN formation in dogs with OS before metastasis. We necropsied and sampled lung tissues from dogs with naturally occurring treatment-naïve OS (n = 15) and control dogs without cancer (n = 10). We further divided dogs with OS into those having lung metastases (n = 5) and those without (n = 10). We stained formalin-fixed paraffin-embedded tissues using multiplex immunofluorescence to quantify the number of bone marrow-derived cells, monocytes and macrophages in the lung samples from each dog. The numbers of CD204+ macrophages, CD206+ macrophages and monocytes and CD11d+ bone marrow-derived cells (BMDCs) were significantly higher in the pre-metastatic lung of dogs with OS (n = 10) than in control dogs without cancer (n = 10). Furthermore, the total nucleated cell (DAPI+) density was higher before metastasis than in healthy lungs. In dogs with established metastases, the number of CD11d+ BMDCs was significantly lower than in the pre-metastatic lung, suggesting this recruitment is transient. Our study provides evidence of PMN existence in a naturally occurring cancer model similar to those observed in pre-clinical murine models. BMDCs are recruited to the lungs before metastases have developed. Dogs with OS may represent ideal candidates for assessing new PMN-targeting therapies.

Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.

Postoperative recurrence of chromophobe renal cell carcinoma is rare, and its metastatic process remains unclear. We here report a case of a solitary metastasis in the residual ureter detected 9 years after the primary surgery and discuss its possible recurrence mechanism based on our immunohistochemical study.

A 67-year-old woman received nephrectomy for a left renal tumor, which was diagnosed as chromophobe renal cell carcinoma with urinary collecting system invasion. Nine years postoperatively, a tumor was found in the residual ureteral stump and was surgically excised. The recurrent tumor was histologically diagnosed as chromophobe renal cell carcinoma surrounded by normal urothelial cells. On immunohistochemical staining, the tumor cells showed a high expression of uroplakin-2, a urothelium-specific marker.

In our case, highly adhesive uroplakin-2-positive cancer cells spilled from the primary site and attached to the residual ureteral stump, growing slowly while being gradually covered by normal urothelial cells.

Although the number of breast cancer deaths has decreased, and there have been developments in targeted therapies and combination treatments for the management of metastatic illness, metastatic breast cancer is still the second most common cause of cancer-related deaths in U.S. women. Numerous phases and a vast number of proteins and signaling molecules are involved in the invasion-metastasis cascade. The tumor cells penetrate and enter the blood or lymphatic vessels, and travel to distant organs via the lymphatic or blood vessels. Tumor cells enter cell cycle arrest, adhere to capillary beds in the target organ, and then disseminate throughout the organ's parenchyma, proliferating and enhancing angiogenesis. Each of these processes is regulated by changes in the expression of different genes, in which lncRNAs play a role in this regulation. Transcripts that are longer than 200 nucleotides and do not translate into proteins are called RNAs. LncRNA molecules, whose function depends on their unique molecular structure, play significant roles in controlling the expression of genes at various epigenetic levels, transcription, and so on. LncRNAs have essential functions in regulating the expression of genes linked to cell development in healthy and pathological processes, specialization, programmed cell death, cell division, invasion, DNA damage, and spread to other parts of the body. A number of cancer types have been shown to exhibit aberrant expression of lncRNAs. In this review, we describe the general characteristics, potential molecular mechanisms and targeted therapy of lncRNAs and discuss the emerging functions of lncRNAs in breast cancer.

DNA logic gates with dynamic nanostructures have made a profound impact on cancer diagnosis and treatment. Through programming the dynamic structure changes of DNA nanodevices, precise molecular recognition with signal amplification and smart therapeutic strategies have been reported. This enhances the specificity and sensitivity of cancer theranostics, and improves diagnosis precision and treatment outcomes. This review explores the basic components of dynamic DNA nanostructures and corresponding DNA logic gates, as well as their applications for cancer diagnosis and therapies. The dynamic DNA nanostructures would contribute to cancer early detection and personalized treatment.

Women diagnosed with early-stage breast cancer can develop metastatic disease following successful initial treatment, with bone being the most common site of metastases. The Breast to Bone (B2B) cohort study of early-stage breast cancer patients was established as a research platform to study the basic biology of breast cancer to bone metastasis and to identify the factors that could improve prevention, early detection and treatment for this debilitating and incurable disease. The B2B cohort includes 478 women diagnosed with incident primary breast cancer (stages I to III) who were recruited from Calgary, Alberta and surrounding areas between February 2010 and July 2015. Four projects have been conducted to date, utilizing data and samples from this cohort. These studies have found the following: (a) women with insufficient or deficient levels of vitamin D (25[OH]D) concentrations in pretreatment serum samples had larger tumors and higher breast cancer grades, (b) several metabolomic biomarkers and cytokines were associated with tumor characteristics and time to recurrence, (c) additional biomarkers were found to be predictive for the high risk of bone metastasis and (d) circulating progastrin (hPG80) was associated with multiple survival outcomes. These research studies and future ones will provide new evidence on bone metastasis etiology in women diagnosed with early-stage breast cancer, improve identification of those at high risk and contribute to personalized treatment and prevention options.

The efficacy of current therapies for ovarian cancer is limited due to the multilevel and complex tumor microenvironment (TME), which induces drug resistance and tumor progression in a single treatment regimen. Additionally, poor targeting and insufficient tissue penetration are important constraints in ovarian cancer treatment.

We constructed PH20-overexpressing cancer-associated fibroblast (CAF)-cancer hybrid-cell membrane vesicles (PH20/CCM) for the dual-targeted delivery of carboplatin (CBP) and siRNA targeting p65 (sip65) loaded on the poly (dimethyl diallyl ammonium chloride) (PDDA)-modified MXene (PMXene), named PMXene@CBP-sip65 (PMCS). The nanoparticle PH20/CCM@PMCS could penetrate the extracellular matrix of tumor tissues and target both cancer cells and CAFs. After tumor cell internalization, these nanoparticles significantly inhibited cancer cell proliferation, generated reactive oxygen species, induced endoplasmic reticulum stress, and triggered immunogenic cell death. After CAF internalization, they inhibited pro-tumor factor release and activated immune effects, promoting immune system infiltration. In an experiment with ID8 homograft-carrying mice, PH20/CCM@PMCS significantly improved tumor inhibition and enhanced immune infiltration in tumor tissues.

These new therapeutic nanoparticles can simultaneously target tumor cells, CAFs, immune cells, and the extracellular matrix, thereby increasing treatment sensitivity and improving the TME. Therefore, these TME-regulating nanoparticles, combining specificity, efficiency, and effectiveness, provide new insights into ovarian cancer treatment.

Metastasis is a major cause of cancer-related deaths. Similar to the tumor microenvironment formation, the premetastatic niche develops in distant organs before the arrival of tumor cells. Elucidating the mechanism(s) underlying premetastatic niche formation could contribute to the establishment of effective therapeutic targets for metastasis. Our research indicates that primary tumors hijack Toll-like receptor 4 (TLR4) signaling to establish a premetastatic niche in the lungs by utilizing an endogenous ligand S100A8. S100A8 is expressed not only in immune cells but also in various types of tumor cells. By focusing on S100A8 as a therapeutic target, we identified at least three multivalent S100A8 inhibitory peptides. Here, we review the tumor-promoting role of S100A8-mediated TLR4 signaling and propose S100A8 as a potential therapeutic target for aggressive cancer.

Bone metastasis is the leading cause of morbidity and mortality in advanced-stage breast cancer patients. While most studies focus on the cellular and genetic factors associated with breast cancer metastasis, the role of the extracellular matrix (ECM) of bone in breast cancer metastasis remains elusive. In this study, we recapitulated the bone microenvironment using in-situ mineralized collagen type-I hydrogels and utilized them to understand breast cancer metastasis. Our results indicated successful mineralization of collagen type-I based hydrogels in the presence of serum proteins, which increased as a function of time. There was no difference in the adhesion of breast cancer cells seeded on collagen and mineralized collagen surfaces. However, there was a marked reduction in cell proliferation, down-regulation of various metastatic markers, and decreased migratory phenotype with a concomitant increase in cleaved caspase-3 on mineralized collagen compared to collagen hydrogels. In conclusion, our results suggest an inverse relationship between bone mineralization and the metastatic propensity of breast cancer cells. We further speculate the role of other factors in the skeletal ecosystem for mediating preferential homing of breast cancer cells to the bone microenvironment.

Advances in molecular biology, genetics, and epigenetics have refined our understanding of metastatic brain cancer and underscored the need for better classification and targeted approaches. The heterogeneity of brain metastases highlights the differences from their primary source of origin and contributes to therapeutic resistance. Before colonising the brain, tumour cells acquire specialised proficiencies that enable them to capitalise on the unique microenvironment of the brain. The tumour cells further orchestrate key adaptations to adjust to the brain microenvironment by manipulating the blood-brain barrier, evading immune surveillance, rewiring metabolic profiles, and reprogramming astrocytes. These adaptations facilitate tumour survival, growth, and treatment resistance. Recognising metastatic brain cancer as a distinctive CNS disease, rather than an extension of the primary cancer, would support the development of rational approaches that target its molecular and genetic features and improve research funding in this area. Here, we delve into the distinct genetic and phenotypic characteristics of metastatic brain cancer, and reflect on how a change in the perception of this disease could accelerate the development of more effective therapies and drive continued progress in the field of neuro-oncology.

Gynecologic cancer, a prevalent and debilitating disease affecting women worldwide, is characterized by the uncontrolled proliferation of cells in the reproductive organs. The complex etiology of gynecologic cancer encompasses multiple subtypes, including cervical, ovarian, uterine, vaginal, and vulvar cancers. Despite optimal treatment strategies, which typically involve cytoreductive surgery and platinum-based chemotherapy, gynecologic cancer frequently exhibits recalcitrant relapse and poor prognosis. Recent studies have underscored the significance of the tumor microenvironment in ovarian carcinogenesis, particularly with regards to the discovery of aberrant genomic, transcriptomic, and proteomic profiles. Within this context, cancer-associated fibroblasts (CAFs) emerge as a crucial component of the stromal cell population, playing a pivotal role in oncogenesis and cancer progression. CAF-derived exosomes, small extracellular vesicles capable of conveying biological information between cells, have been implicated in a range of tumor-related processes, including tumorigenesis, cell proliferation, metastasis, drug resistance, and immune responses. Furthermore, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins has been found to strongly correlate with clinical and pathological characteristics of gynecologic cancer patients. Our review provides a novel perspective on the role of CAF-derived exosomes in gynecologic cancer, highlighting their potential as diagnostic biomarkers and therapeutic targets.

Background/Objectives: Douglasectomy is defined as the removal of the pelvic peritoneum of the entire pouch of Douglas. In presumed FIGO stage I ovarian cancer, isolated microscopic cancer cells might disseminate from the ovaries to their neighboring pelvic peritoneum. However, a simple hysterectomy with bilateral salpingo-oophorectomy and a staging procedure is the standard of care. This study aims to investigate the safety and feasibility of douglasectomy compared to random pelvic biopsies, and it is based on the survival of patients with early ovarian cancer. Methods: We retrospectively analyzed the records of patients with presumed 2018 FIGO stage I ovarian cancer who underwent surgery in the 1st Department of Obstetrics and Gynecology Clinic from 2012 to 2022. Patient characteristics and oncological and follow-up information were collected. Results: A total of 88 patients were categorized into two groups, namely Group A (27 patients) with douglasectomy and Group B (61 patients) with random biopsies. There was no statistically significant difference in age, BMI, comorbidities, FIGO stage, intraoperative blood loss, and ICU admittance between the two groups. Conversely, patients with en bloc hysterectomy-douglasectomy had statistically significant higher pre-operative CA-125 values, surgery duration, rate of postoperative complications, and hospital stay. Concerning survival rates, there was a statistically significant difference in disease-free survival (p = 0.033), but no difference was observed in overall survival (p = 0.66). Conclusions: En bloc removal of the pelvic peritoneum of the entire pouch of Douglas with the uterus is a safe and feasible technique during surgery for early ovarian cancer, which leads to improved disease-free survival and local control.

Brain metastases (BMs) from endometrial cancer (EC) are rare and challenging to treat, with limited standardized guidelines. This systematic review aims to evaluate the incidence, therapeutic strategies, and outcomes associated with brain metastases in EC patients, offering insights for clinical practice and future research.

A comprehensive literature search was conducted using PRISMA guidelines, including PUBMED up to October 2024. Reports reporting individual or aggregate data on EC brain metastases were included. Descriptive and quantitative analyses were performed on incidence, treatment modalities, and survival outcomes. Three reports that used data from the Surveillance, Epidemiology, and End Results and National Cancer Database were used only to assess the incidence of brain metastases from endometrial carcinoma.

From 911 reports identified, we included 99 reports, identifying 594 cases; these and the case of a patient with brain metastasis from endometrial carcinoma followed at our center were used for analysis of disease characteristics; incidence; and treatment modalities, such as surgery, radiotherapy, chemotherapy, and combinations. Survival outcomes were influenced by treatment type and disease characteristics, with multimodal approaches showing improved outcomes.

This review underscores the rarity of EC brain metastases and highlights the need for tailored, multimodal treatment strategies. Future research should focus on prospective trials and molecular profiling to optimize management.

Background/objectives: Despite the incremental improvement of survival with systemic therapy in metastatic gastric cancer (GC), the outcomes of patients with peritoneal carcinomatosis (PC) remain poor. The limited effectiveness of systemic therapy is attributed to the blood-peritoneal barrier and anarchic intra-tumoral circulation, which reduce the penetration of systemic therapy. Approaches that incorporate intraperitoneal (IP) chemotherapy, in addition to systemic therapies, may be a viable alternate strategy. Therefore, we provide a review of biology of gastric cancer peritoneal metastasis and evidence for bidirectional iterative IP chemotherapy in GCPC. Methods: A comprehensive search in PubMed, Scopus, Embase, Web of Science, Google Scholar, and ClinicalTrials.gov was performed to find the relevant articles and ongoing phase II/III clinical trials in iterative IP chemotherapy in GCPC. Results: Intraperitoneal (IP) chemotherapy leverages the blood-peritoneal barrier to allow for the administration of high concentrations of chemotherapy directly to the peritoneal metastases, with a significant reduction in the systemic toxicity and enhanced drug efficacy against peritoneal metastasis. This pharmacokinetic advantage of IP chemotherapy can be further enhanced by additional measures such as heat or aerosolization. There are three IP chemotherapy approaches, namely, heated intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosolized chemotherapy (PIPAC), and normothermic intraperitoneal chemotherapy (NIPEC). Recent evidence suggests that iterative IP chemotherapy combined with systemic therapy may offer significant survival benefits for patients with peritoneal metastasis. Furthermore, bidirectional treatment approaches may also increase the chances of surgical resection and survival. Conclusions: IP chemotherapy plays a pivotal role in the management of gastric carcinomatosis, particularly in combination with cytoreduction in highly selected patients. The combination of systemic and regional control may increase the chances of surgical resection and may ultimately lead to significant survival benefits.

Metachronous metastasis occurs many years later in cases of hormone-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, with the most common sites being the lymph nodes, bones, liver, lungs, and brain. The late recurrence of estrogen receptor (ER)-positive breast cancer is attributed to prolonged adjuvant therapy and the high expression of dormancy-associated genes, allowing cancer cells to survive for decades without proliferating. It is a form of chronic breast cancer that remains asymptomatic, with no clinical signs of progression or recurrence. Estrogen receptor-negative breast cancers, on the other hand, have no long-term tumor dormancy due to their fast growth and low expression of dormancy-related genes. Adrenal gland metastasis, particularly as an oligometastatic presentation, is exceedingly rare, and optimal treatment strategies remain elusive. In this report, we present a case demonstrating long-term survival after treatment of adrenal gland metastasis, accompanied by a comprehensive literature review. At the age of 48, our patient was diagnosed with invasive ductal carcinoma of the left breast. Treatment included breast-conserving surgery, radiotherapy, and adjuvant hormone therapy. Ten years later, she developed a solitary left adrenal metastasis. Treatment included laparoscopic adrenalectomy and a change in hormonal therapy. Our patient is currently still asymptomatic with no evidence of disease. Her overall survival of over 20 years is exceptional. Resection of the adrenal metastasis combined with systemic hormonal therapy represents the recommended approach for this metachronous metastasis. In the contemporary context, antihormonal therapy in combination with CDK4/6 inhibitors should be considered. The present case underscores the necessity of establishing a lifelong (inter)national cancer registry to document rare recurrences systematically. Such a registry would provide insights into the prevalence of uncommon scenarios and offer invaluable data on proposed treatments, facilitating the development of uniform treatment strategies.

Triple-negative breast cancer (TNBC) constitutes for 10-15% of all breast cancer cases. Tumor heterogeneity, high invasiveness, distant metastasis, lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 expression contribute to TNBC associated with poor overall survival outcomes amongst diseased individuals. The disparity in clinico-pathological and metastatic patterns to distant sites has substantially enhanced the incidences of tumor recurrence. Survival outcomes amongst metastatic TNBC patients are worse in comparison to non-metastatic TNBC counterparts. MicroRNAs (miRNAs) have emerged as significant drivers to function either as oncogene or tumor suppressors by exerting modulating effects on the expression of target genes in the TNBC tumor microenvironment. The pleiotropic nature of miRNAs expands their preclinical and clinical utility in combating both metastatic and non-metastatic TNBC cases and thereby improves their survival outcomes. The present review article aims to highlight the varying survival outcomes in metastatic and non-metastatic TNBC cases. The present review article emphasizes the therapeutic and prognostic potential of miRNAs in TNBC to improve survival outcomes by retarding distant metastasis to lung, bone, brain, and lymph nodes.

The view of neutrophils has shifted from simple phagocytic cells, whose main function is to kill pathogens, to very complex cells that are also involved in immune regulation and tissue repair. These cells are essential for maintaining and regaining tissue homeostasis. Neutrophils can be viewed as double-edged swords in a range of situations. The potent killing machinery necessary for immune responses to pathogens can easily lead to collateral damage to host tissues when inappropriately controlled. Furthermore, some subtypes of neutrophils are potent pathogen killers, whereas others are immunosuppressive or can aid in tissue healing. Finally, in tumor immunology, many examples of both protumorigenic and antitumorigenic properties of neutrophils have been described. This has important consequences for cancer therapy, as targeting neutrophils can lead to either suppressed or stimulated antitumor responses. This review will discuss the current knowledge regarding the pro- and antitumorigenic roles of neutrophils, leading to the concept of a confused state of neutrophil-driven pro-/antitumor responses.