The development and changes of the tumor microenvironment in cancers
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The development and changes of the tumor microenvironment in cancers
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The development and changes of the tumor microenvironment in cancers.
Our understanding of cancer has changed fundamentally over the past few decades. We now recognize that cancer is not just a disease but a complex ecosystem involving a wide range of non-cancerous cells and their myriad interactions within tumors.
The tumor microenvironment ( TME ) includes multiple immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various other tissue-recipient cell types.
These host cells were once thought to be bystanders of tumorigenesis but are now known to play key roles in the pathogenesis of cancer.
The cellular composition and functional state of the TME can vary greatly depending on the organ in which the tumor occurs, intrinsic features of the cancer cell, tumor stage, and patient characteristics.
Understanding the importance of TME at various stages from tumor initiation, progression, invasion to metastatic dissemination and growth, and understanding the complex interactions between tumor cell-intrinsic, extracellular, and systemic mediators of disease progression are essential for the rational development of effective anticancer agents. Cancer treatment is critical.
Basic principles of TME formation
Cancer cells orchestrate a supportive tumor environment by recruiting and reprogramming noncancerous host cells and remodeling the vasculature and extracellular matrix ( ECM ).
This dynamic process relies on heterotypic interactions between cancer cells and TME resident or recruited noncancerous cells.
There are multiple mechanisms that regulate this cell-cell dialogue, including through cell-cell contacts and paracrine signaling.
Contact-dependent communication is mediated by adhesion molecules, including integrins, cadherins, selectins, and members of the immunoglobulin superfamily, and also through gap junctions and membrane protein channels.
In addition to direct cell – cell contacts, paracrine signaling through the release of cytokines, chemokines, growth factors, and proteases is also critical for intercellular communication within the TME .
Secreted in response to cancer-intrinsic features and cellular stress, these molecules can originate from a variety of cell types in the TME and exert direct and indirect effects on target cells through receptor binding or ECM remodeling.
The ECM facilitates intercellular communication by acting as a matrix for secreted molecules and a substrate for cell adhesion and migration.
Remodeling of the ECM by proteases releases the tethered molecules, resulting in locally high concentrations of release mediators.
In addition, cancer and TME cells directly contact the surrounding ECM through receptors including integrins and CD44 , thus forming a complex signaling network in cancer.
The composition and functional status of the TME can vary substantially between patients, even within the same cancer type. Patient-specific factors, including age, sex, lifestyle, body mass index, and microbiome, can affect the TME , as can the organ in which the tumor occurs . Different organs have unique tissue-innate immune and stromal cell types, and tissue type can determine the functional status of these cells.
Apart from anatomical site-dependent mechanisms, perhaps the most important regulators of the TME are the cancer cells themselves.
The cell-intrinsic features of cancer, including altered ( epi )genetics, metabolic reprogramming and deregulated signaling, are key determinants of how tumors shape their microenvironment.
With the rapid development of high-resolution analysis techniques, more links between cancer-intrinsic features and TME will be revealed, which may lay the foundation for the rational design of TME-targeting strategies for individual tumors.
Tumor initiation: disruption of tissue homeostasis
Malignant cells must overcome multiple nodes to successfully form tumors, many of which depend on normalizing signals that disrupt surrounding tissue and then hijack microenvironmental processes to support the developing tumor.
Balance from Immune Attack to Immune Evasion
Our immune system is critical for fighting off life-threatening pathogens, healing wounds and eradicating damaged cells. To carry out these functions, the immune system is incredibly diverse and adaptable, with tightly controlled mechanisms to limit tissue damage and restore homeostasis.
Analysis of cancer evolution revealed that initially low-grade lesions were characterized by an influx of naive T cells, suggesting that the immune system sensed transformation at its earliest stages.
However, as the lesion progressed, a shift in the accumulation of activated T cells and myeloid cells was observed, as well as an upregulation of genes involved in immunosuppression.
Activated CD8+ T cells decreased, PD-L1 and CTLA4 expression increased, regulatory T cells ( Tregs ) increased, and T cell receptor ( TCR ) clone types decreased. As these lesions progress, a shift to an immunosuppressive TME ensues.
In the early stages of tumorigenesis, primary tumors result in a supportive inflammatory environment, and almost all progressive tumors induce varying levels of T cells, natural killer (NK) cells, and DC rejection or triggering of CD8 + T cells Handicap procedure.
When tumors simultaneously stimulate the recruitment and activation of myeloid cells, particularly macrophages and neutrophils, both types of cells together form a tumor-supportive inflammatory environment.
Inflammation: a catalyst for tumor progression
In developing tumors, inflammation is characterized by crosstalk that destroys adaptive innate immune cells. This inflammation can become chronic and destructive under the influence of prolonged inflammatory signaling, hypoxia, low pH, and altered metabolite levels.
As tumors grow, the co-evolved immune environment undergoes profound changes, resulting in decreased cytotoxic CD8+ T cells and NK cells, dysfunctional CD8+ T lymphocytes, immunosuppressive CD4+FoxP3+ Tregs, and regulatory B Cells progressively increased, while CD4+ T cells were skewed toward a pro-inflammatory Th2 phenotype, and DCs exhibited maturation and functional defects.
At the same time, myeloid cells are increasingly mobilized to the TME, where they adapt their phenotype to local inflammation.
Tumor-associated macrophages ( TAMs ) and neutrophils ( TANs ) are usually the most abundant myeloid cells in different TMEs. Key tumor-derived mediators driving the mobilization and activation of these cells include CSF-1, CCL2, VEGF-A, TNF-α, and semaphorin 3A, G-CSF, GM-CSF, IL-6, CXCL1, CXCL2, IL-1β and IL-8 in neutrophils.
Their presence in human tumors is often associated with poorer prognosis and poorer response to therapy.
Multifaceted roles of CAFs and ECM in TME development
Together with immune cells, CAFs are major components of many tumors. Some tumors, such as hepatocellular carcinoma, arise from abnormally activated fibroblasts, especially in fibrotic or cirrhotic livers.
Other types of cancer can also induce fibrosis, and recent advances in single-cell technologies have revealed previously unappreciated phenotypic and functional diversity of CAFs .
CAFs also exhibit plasticity to dynamic changes in the TME. Recent studies have shown that CAFs consist of multiple isoforms that change during tumor progression and are spatially regulated.
In pancreatic cancer, three distinct subtypes of CAFs coexist: myofibroblast (myCAF ) , inflammatory CAF ( iCAF ), and antigen-presenting CAF ( apCAF ), with distinct functions and transcriptome plasticity. Similar CAF subpopulations have also been identified in other cancer types.
Recent studies have shown that CAFs can help tumors evade immune control through multiple mechanisms. CAFs are primarily responsible for the deposition and remodeling of the ECM within the TME .
CAFs create a physical barrier to ECM deposition by secreting CXCL12 and TGF-β , directly preventing T cell recruitment or activation.
In addition, CAFs also mobilize and program immunosuppressive myeloid cells by secreting mediators including IL-6 , IL-1β , VEGF , CSF-1 , CCL2 , indirectly interfere with anti-tumor immunity, and exert immune function by promoting the accumulation of Tregs inhibitory activity.
CAFs also directly affect cancer cells. In human breast and lung cancer samples, the CD10+GPR77+CAF subpopulation provides a living space for cancer stem cells by secreting IL-6 and IL-8 , thereby promoting tumor formation and chemotherapy resistance.
Angiogenesis drives cancer progression
Angiogenesis, the process of developing new blood vessels, is critical to tumorigenesis.
Angiogenesis is a complex process involving extensive crosstalk between endothelial cells, pericytes, parietal cells, cancer cells, tumor-associated immune cells, and CAFs .
Tumor blood vessels are constantly exposed to pro-angiogenic factors, resulting in disorganized, leaky, and tortuous vasculature.
This affects tumor oxygenation, alters immune cell dynamics, and reduces drug penetration into tumors.
Tissue hypoxia is the main cause of angiogenesis. Many molecules that respond to hypoxia can promote the angiogenic switch, with vascular endothelial growth factor ( VEGF ) and its downstream signaling pathways being the main drivers.
In addition, tumor-associated myeloid cells promote tumor angiogenesis and increase vascular permeability through pro-angiogenic mediators, including VEGF-A, FGF2, PIGF, TNF, and BV8.
These cells also produce proteases, such as MMPs and cathepsins, that break down the ECM and release sequestered pro-angiogenic molecules, making them bioavailable.
Importantly, the interactions between the vasculature and immune cells are reciprocal.
Accumulating evidence suggests that tumor-induced angiogenesis contributes to immunosuppression and immune evasion.
For example, vascular adhesion molecules that regulate immune cell homing and trafficking can be downregulated, and tumor-associated endothelial cells express lower levels of ICAM-1 , VCAM-1 , E- selectin, and P- selectin.
Conversely, inhibitory immune checkpoint molecules including IDO , TIM3 , and PD-L1 can be upregulated on tumor blood vessels.
Tumor progression: invasion and migration of cancer cells
Once tumors have successfully established a mutually reinforcing link between angiogenesis, inflammation, and fibrosis, they can proceed to the next stage of disease progression: local invasion. Invasive growth is one of the main hallmarks of cancer, setting the stage for metastatic dissemination.
Invasion is a complex multistep process in which epithelial cell-cell adhesions must be disrupted in order to separate from neighboring cancer cells.
Loss of the intercellular adhesion protein ( E-cadherin ) is central to this process, often accompanied by an epithelial-mesenchymal ( EMT )-like transition state.
Factors derived from the TME promote phenotypic switching of cancer cells leading to local invasion.
Furthermore, accumulating evidence suggests that CAFs generate trajectories in the ECM through their remodeling and exertion of physical pull, thereby enabling collective invasion of cancer cells.
Other TME cells can also promote cancer cell invasion. For example, intravital microscopy ( IVM ) studies performed in a mouse breast cancer model demonstrated that the invasion and migration of EGFR+ cancer cells depend on the co-migration of EGF-producing TAMs.
These findings suggest that CAFs, immune cells, and tissue-resident cells work together to promote the invasive behavior of cancer cells.
The next rate-limiting step in the metastasis process is the injection of cancer cells into the blood or lymphatic circulation.
The mechanism by which cancer cells enter the circulation across the endothelial layer is complex, environment-dependent, and influenced by intrinsic characteristics of cancer cells, properties of the ECM and type of vasculature, microenvironmental factors, and degree of hypoxia. Typically, TAMs are associated with cancer cell perfusion.
Perivascular TIE2+ TAM – induced VEGF-A signaling results in a localized loss of vascular junctions, resulting in a transient increase in vascular permeability that promotes cancer cell perfusion.
Furthermore, in addition to macrophages and endothelial cells, neutrophils, pericytes, CAFs , adipocytes, and mechanical features of the TME , including ECM structure and interstitial fluid pressure, also affect cancer cell perfusion through direct or indirect mechanisms.
Tumor metastasis: formation of a pre-metastatic niche
The impact of developing tumors on the host is not limited to the local TME .
Through paracrine effects, the primary tumor triggers a cascade of events that creates a cancer cell-conducting microenvironment in distant organs, followed by metastatic spread.
Initiation signals that trigger a cascade of systemic changes leading to the generation of the pre-metastatic niche include tumor-derived soluble mediators, most notably G-CSF, VEGF-A, PLGF, TGF-β, S100 proteins, and TNF, and tumor- With EVs , these tumor messages can be transferred to BM cells and resident cells in distant organs, where they activate and program immune cells and their progenitors for mobilization to future metastatic sites.
Mediators secreted by other tumors can directly modify distant organs. For example, hypoxic 4T1 breast cancer cells secrete LOX, which disrupts normal bone homeostasis and promotes the homing and colonization of circulating tumor cells ( CTCs ) by inducing osteoclastogenesis.
In LLC and B16 tumor-bearing mice, tumor-derived EVs carrying small RNAs activate Toll-like receptor 3 ( TLR3 ) in lung epithelial cells, stimulating the release of neutrophil chemotactic mediators through neutrophil recruitment Eventually the lung pre-metastatic niche is formed.
These studies suggest that primary tumors disrupt the crosstalk between different tissue-resident cells and newly mobilized BM-derived immune cells in distant organs, thus contributing to the formation of a pre-metastatic niche.
Another mechanism by which primary tumors promote the metastatic niche is through tumor-induced systemic inflammation and immunosuppression, favoring immune evasion of spreading cancer cells.
In a mouse model of breast cancer, systemic mobilization of IL-1β -secreting neutrophils enhanced the secretion of prostaglandin E3 from adventitial fibroblasts , resulting in decreased antitumor immunity and enhanced lung metastasis.
CTC’s battle for survival in the loop
Once tumor cells invade the circulation, they are immediately exposed to a series of different survival challenges in this foreign microenvironment. Including anoikis caused by cell detachment, high shear stress in the blood circulation, and immune-mediated attack, these together lead to the death of most CTCs .
Nonetheless , for the small fraction of CTCs that survive circulation , they can evade destruction through various mechanisms.
These include CTC aggregation, which promotes stemness by inducing NANOG , SOX2 , and OCT ; binding to specific immune cells such as neutrophils or platelets; and thereby evading the action of cytotoxic immune cells including NK cells.
Consistent with these mechanisms, CTC aggregates are generally associated with poorer patient outcomes compared with single CTCs , whereas a high ratio of circulating neutrophils to lymphocytes is associated with poor prognosis in a variety of cancers.
Organ tropism and extravasation
For the small fraction of CTCs that survive through circulation , the next rate-limiting step in their metastatic process is extravasation into metastatic organs.
This depends in part on the underlying organ tropism of each primary cancer.
Metastasis can be highly stereotyped, for example, breast cancer spreads predominantly to the lung, liver, bone, and brain, whereas prostate cancer shows a high propensity to spread to the bone.
This organ tropism is influenced by multiple mechanisms, including signaling of factors such as chemokines, metabolites, and EVs , which contribute to the directed migration of CTCs to specific organs.
In addition, the specific circulation routes taken by CTCs and the range of different vascular barriers that cancer cells must cross in order to gain access to specific organs further influence their final destination.
For the extravasation process itself, tumor cells must first come to rest and attach to the endothelial lumen while being constantly subjected to high shear forces from the surrounding fast-flowing blood.
Cell adhesion molecules and their ligands, integrins, and ECM components expressed by tumor cells and endothelial cells facilitate this step and share some similarities with the molecular mechanisms underlying blood leukocyte rolling, adhesion, and extravasation.
Platelets and neutrophils may still disseminate with CTCs, which can further enhance tumor cell adhesion to the vasculature through selectins, GPCRs, or through the production of neutrophil extracellular traps ( NETs ), respectively.
After adhesion, CTCs next traverse EC junctions, and possibly additional vascular cell layers and the ECM , into the new organ parenchyma, which often requires active proteolysis or degradation of cell adhesion molecules.
Cancer cells not only depend on the proteases and degradative enzymes produced during this step, but also release these enzymes from non-cancerous cells, including platelets, monocytes, and neutrophils, through the production of NETs .
After extravasation, CTCs usually remain near blood vessels, which is critical in determining their fate.
Tumor dormancy and growth at metastatic sites
After extravasation to secondary sites, disseminated tumor cells ( DTCs ) face a new set of challenges from the foreign tissue environment, and the vast majority of tumor cells are again killed by host defense mechanisms, including immune surveillance.
The few DTCs that survive to grow new organs usually remain near the vasculature, and molecular signals from the perivascular niche ( PVN ) and tissue-specific niches initially keep DTCs in a dormant state, which may protect them from Recognition and killing by the immune system.
Dormancy is the least understood stage of the metastatic cascade, and these cells stop proliferating and can survive in a quiescent state, sometimes for years to decades.
Studies of the mechanisms controlling the onset of dormancy, its maintenance during latency, and its reactivation after dormancy remain a ” black box ” in the field of cancer .
It is therefore necessary to fully understand its underlying mechanisms, especially key interactions with the microenvironment, for this fine regulation of organ-specific metastasis.
Summary: The development and changes of the tumor microenvironment in cancers
As the scope and understanding of the tumor microenvironment has grown in recent years, we have come to appreciate the enormous complexity and interconnectedness of the TME, as well as its diversity across different organs and patients.
Despite these challenges, therapeutic strategies targeting the TME are expanding and showing promising prospects.
These include therapies that “reprogram” the TME through interventions that alter the ECM, EVs, cell therapies and vaccines, and immune checkpoint inhibitors.
The key question now is how to combine these different approaches in a rational and optimal way.
Looking ahead, with the technological breakthroughs in single-cell analysis technology and artificial intelligence, research on TME will make key progress in the next few years to fully realize TME -targeted cancer therapy.
We believe that in the near future, we will be able to use TME as a therapeutic target to benefit more cancer patients.
references:
1. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023 Mar 13;41(3):374-403
The development and changes of the tumor microenvironment in cancers
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