Metastatic disease is the major challenge of cancer that accounts for over 90% of total cancer lethality. Mounting clinical and preclinical data now indicate that inflammation, a potent immune and ...repair response, is indispensable for metastasis. In this review we describe our current understanding of how major inflammatory cells contribute to metastatic cascade with a focus on the primary tumour. We also discuss exciting new directions for future research and novel therapeutic approaches to tackle metastatic disease through targeting inflammation.
There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation, they create an inflammatory environment that is ...mutagenic and promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration and invasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissue for arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets.
Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the ...recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells.
Display omitted
Metastasis to bone frequently occurs in majority of patients with advanced breast cancer and prostate cancer, leading to devastating skeletal-related events and substantially reducing ...the survival of patients. Currently, the crosstalk between tumor cells and the bone stromal compartment was widely investigated for bone metastasis and the resistance to many conventional therapeutic methods. Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein 1), a secreted and chemokine-like glyco-phosphoprotein is involved in tumor progression such as cell proliferation, angiogenesis, and metastasis. The expression of OPN in tumor tissue and plasma has been clinically proved to be correlated to poor prognosis and shortened survival in patients with breast cancer and prostate cancer. This review summarizes the multifaceted roles that OPN plays in bone microenvironment and drug resistance, with emphasis on breast and prostate cancers, via binding to αvβ3 integrin and CD44 receptor and inducing signaling cascades. We further discuss the promising therapeutic strategy for OPN targeting, mainly inhibiting OPN at transcriptional or protein level or blocking it binding to receptor or its downstream signaling pathways. The comprehending of the function of OPN in bone microenvironment is crucial for the development of novel biomarker and potential therapeutic target for the diagnosis and treatment of bone metastasis and against the emergence of drug resistance in advanced cancers.
Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited ...by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.
•The design principles and synthesis strategies of host–guest MOFs is logically reviewed.•The properties and applications of host–guest MOFs originating from synergistic effect are ...demonstrated.•Further development of host–guest MOFs is suggested.
Metal–organic frameworks (MOFs) as a class of unique porous crystalline materials have developed rapidly in the past decades. The unique features of component diversities, structural designability, and tunable porosities of MOFs endow them inherent superiorities as hosts to accommodate diverse species of guests. The resulting host–guest MOFs reveal a variety of properties and applications, which could be readily modulated through the tuning of the host, the guest, and the host–guest interactions. Therefore, the host–guest MOFs have attracted much attention and become a hot topic for research. This review will concentrate on the recent progress of host–guest MOFs. The achievements and understanding of host–guest MOF, including the components of host–guest systems, the types of species interactions, and the characterization methods have been reviewed and discussed. Based on this, the design and tuning principles for the construction of host–guest MOFs have been highlighted. The recently typical examples of function-oriented construction of host–guest MOF for various properties including optical, electrical, and catalytic properties have been overviewed. Furthermore, the challenges and perspectives of developing host–guest MOF materials have been generalized.
The Al effect on the electrochemical properties of layered double hydroxides (LDHs) is not properly probed, although it is demonstrated to notably promote the capacitive behavior of LDHs. Herein, ...ternary NiCo2Alx layered double hydroxides with varying levels of Al stoichiometry are purposely developed, grown directly on mechanically flexible and electrically conducting carbon cloth (CC@NiCo2Alx‐LDH). Al plays a significant role in determining the structure, morphology, and electrochemical behavior of NiCo2Alx‐LDHs. At an increasing level of Al in NiCo2Alx‐LDHs, there is a steady evolution from 1D nanowire to 2D nanosheets. The CC@NiCo2Al‐LDH at an appropriate level of Al and with the nanowire–nanosheet mixed morphology exhibits both significantly enhanced electrochemical performance and excellent structural stability, with about a 2.3‐fold capacitance of NiCo2‐OH. When applied as the anode in a flexible asymmetric supercapacitor (ASC), the CC@NiCo2Al‐LDH gives rise to a remarkable energy density of 44 Wh kg−1 at the power density of 462 W kg−1, together with remarkable cyclic stability with 91.2% capacitance retention over 15 000 charge–discharge cycles. The present study demonstrates a new pathway to significantly improve the electrochemical performance and stability of transition metal LDHs, which are otherwise unstable in structure and poorly performing in both rate and cycling capability.
A flexible asymmetric supercapacitor device is fabricated by using CC@NiCo2Al‐LDH with mixed morphologies of 1D nanowires and 2D nanosheets as the positive electrode. ZIF‐8 derived porous carbon (ZPC), PVA/KOH, and filter paper serve as the negative electrode, solid‐state electrolyte, and seperator, respectively. The device exhibits an energy density of 44 Wh kg−1 at 462 W kg−1.
Tumor-associated macrophages (TAMs) have multiple potent functions in cancer and, thus, represent important therapeutic targets. These diverse functions highlight the heterogenous nature of TAMs. ...Recent single cell omics technologies have significantly advanced our understanding of the molecular diversity of TAMs. However, a unifying nomenclature of TAM diversity and annotation of their molecular signatures is lacking. Here, we review recent major studies of single cell transcriptome, epigenome, metabolome, and spatial omics of cancer with a specific focus on TAMs. We also propose a consensus model of TAM diversity and present avenues for future research.
TAMs have diverse functions in cancer, reflecting the heterogenous nature of these immune cells. Here, we propose a new nomenclature to identify TAM subsets.Recent single cell multi-omics technologies, which allow the clustering of TAM subsets in an unbiased manner, have significantly advanced our understanding of the molecular diversity of TAMs in mice and humans.Novel mechanisms and potential therapeutic targets have been identified that might regulate the tumor-promoting function of different TAM subsets.TAM diversity opens promising therapeutic opportunities for envisaging putative cancer treatments.
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a ...multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.
Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the ...cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.
PDF
