May 28, 2022

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Mitochondrial transfer between cells in the tumor microenvironment

Mitochondrial transfer between cells in the tumor microenvironment

 

Mitochondrial transfer between cells in the tumor microenvironment.  Intercellular communication is the basic process of every multicellular organism.

In addition to membrane binding and releasing factors, the sharing of cytoplasmic components represents a new and underexplored signaling pathway.

The direct transport of mitochondria between cells is a special example of this communication channel.

In 2020, Sahinbegovic H et al. published a review titled “Intercellular Mitochondrial Transfer in the Tumor Microenvironment” in “Cancers”, discussing how cancer cells use mitochondrial transfer between cells to maintain their high metabolic demands and promote drug resistance, and describes relevant molecules in current and future cancer treatments. The brief introduction is as follows:

 

 

Background

Most human cells use mitochondria as the main source of energy and metabolites. However, a typical cancer cell tends to up-regulate glycolysis, a hypothesis put forward by Otto Waberg more than 100 years ago. Glycolysis produces fewer ATP molecules and results in continuous acidification of the extracellular space by increasing the production of lactic acid. However, the increase in glycolysis rate contributes to the development of some cancer features, for example, by inhibiting oxidative phosphorylation (OXPHOS) to avoid apoptosis. The ability to die, and promote metastasis and diffusion through the degradation of the extracellular matrix and tissue growth. In addition, tumor cells usually survive in hypoxic environments and rely on anaerobic glycolysis to produce energy. Therefore, forcing tumor cells to OXPHOS instead of glycolysis has become a promising treatment strategy.


The influence of the microenvironment on tumor cells is very complex, often including the direct participation of tumor mitochondria. Cancer cells can release the entire mitochondria (at the time of necrosis) or its components, such as mitochondrial DNA (mtDNA), ATP, cytochrome C or formylated peptides, into the extracellular space to become damage-related molecular patterns (DAMP) and activate immune cells , To produce pro-inflammatory and immunosuppressive responses to inhibit or stimulate tumor growth and/or metastasis.


The regulation of tumor mitochondria is an important mechanism for tumor cells to get rid of the control of the immune system and develop drug resistance. In addition to tumor cells and immune cells, the tumor microenvironment also contains many different cell types, which can be directly controlled by cell-cell contact or indirectly controlled by the secretion of soluble factors and various extracellular vesicles. Recently, a new cell-to-cell communication mechanism based on the horizontal transfer of mitochondria between non-tumor cells and malignant cells was reported, which triggered new thinking about whether the phenomenon of direct mitochondrial sharing would cause malignant cells to develop resistance to existing drug combinations. And promote tumor growth. At present, little is known about the sharing of intracellular molecules and organelles. With the deepening of research, it may explain the reasons for the failure of many treatments and eventually form new and more effective drug combinations.

 

 


Mitochondrial transfer method

Mitochondrial metastasis was first discovered in 2006. Mitochondria from bone marrow stromal cells (BMSCs), rather than free mitochondria or mitochondrial DNA, can migrate to mitochondrial-deficient A549 lung cancer cells and restore their aerobic respiration. A follow-up study further supports the regulated exchange directionality of the donor, unirradiated PC12 cells with defective mitochondria cannot nourish the recipient PC12 cells and resurrect them. In vivo injection into mouse melanoma cells expressing fluorescently labeled mitochondrial protein, mitochondrial metastasis was also observed.


Basic research on the physiological relevance of mitochondrial transfer has shown that mitochondrial transfer is of great significance in the regeneration of damaged or infected tissues. The “mitochondrial healing” theory was subsequently supported by further studies of various tissues, including blood vessels, brain, lung, cornea, and other tissues. In the immune system, the transfer of mitochondria has also been described as fighting bacterial infections. The presence of pathogens in immune cells is usually accompanied by a transition from glycolytic metabolism to OXPHOS as a means to trigger a rapid antimicrobial response. During acute respiratory distress syndrome, macrophages acquire additional mitochondria through surrounding mesenchymal stem cells (MSCs) to enhance their anti-inflammatory and phagocytic abilities. This is a notable example of an infection-induced metabolic switch. Therefore, the importance of mitochondrial exchange in maintaining tissue homeostasis is unquestionable. However, the shuttle of mitochondria between cells may also have serious pathological consequences, especially in cancer, where cancer cells often use the surrounding environment (Figure 1).

Mitochondrial transfer between cells in the tumor microenvironment
Figure 1 Hypothetical effects of mitochondrial metastasis on injured cells and cancer cells

 

The exact mechanism of mitochondrial transfer is still unclear. So far, only a few key molecules have been involved in this process. High OXPHOS requirements and/or severe mitochondrial damage are typical features of recipient cells. To initiate metastasis, the donor cell must not only have undamaged healthy mitochondria, but also be specially activated. Metalloproteinase-1 (MMP-1), nestin and pro-inflammatory cytokines have been identified as necessary factors to stimulate the release of mitochondria from donor cells. When cultured with leukemia cells, donor BMSCs showed elevated levels of PGC1α, which is the main regulator of mitochondrial biogenesis necessary for effective mitochondrial transfer. The activation of donor function is usually related to the increase of intracellular reactive oxygen species (ROS) produced by recipient cells.

 

 


Tunnel nanotubes are the main transport route of mitochondria

Adjacent cells can share mitochondria through a variety of mechanisms, including: (i) formation of extracellular carriers (EVs), (ii) tunnel nanotubes (TNTs) formed at physical contact sites, (iii) mitochondrial discharge, (ⅳ) ) Cytoplasmic fusion. A number of studies have shown that in healthy tissues and tumor tissues, TNTs (ultra-fine cytoplasmic bridges between cells) are the main delivery system of mitochondria (Figure 2). It also describes mitochondrial sharing that does not rely on TNT in certain tumors. However, there are relatively few such examples, and more research on the transfer mechanism is needed.

Mitochondrial transfer between cells in the tumor microenvironment
Figure 2 Schematic diagram of mitochondrial transfer through tunneled nanotubes

 

In order to transport mitochondria efficiently, functional microtubules and related molecular motors are required, especially myosin X and myosin Va co-localize with mitochondria in TNTs. Some donor cells highly express small GTPase Miro1 in the outer mitochondrial membrane. In MSCs cultured in LA-4 epithelial cells, when Miro1 was depleted, mitochondrial transfer was ineffective, and overexpression of Miro1 increased the ability of MSCs to donate mitochondria. Mechanistically, Miro1 seems to coordinate the movement of mitochondria along microtubules by promoting the assembly of a complex molecular motor.


The role of TNT in localizing actin in mitochondrial exchange is unclear. It is well known that filamentous actin hinders the passive transfer of soluble cytoplasmic molecules through TNTs and acts as a scaffold to stabilize the structure of TNT. The actin binding protein M-Sec has been shown to be very important for the formation of TNTs in macrophages and the intercellular proliferation of Ca2+. The increase in Ca2+ level activates Mirol, which is localized in mitochondria, and further binds to microtubule-related motor proteins.


CD38 is an extracellular enzyme involved in cell transmembrane signal transduction and cell adhesion. In recent years, it has been considered as one of the key enzymes for mitochondrial transfer. In addition to its receptor function, CD38 also regulates intracellular Ca2+ levels by producing cyclic ADP ribose. The Ca2+ regulation of CD38 seems to be important for the transmission of mitochondria from BMSCs to myeloma cells and from astrocytes to neurons in stroke-damaged tissues, although this transmission occurs through different mechanisms (TNTs and TNTs, respectively). EVs). Therefore, the increase of intracellular Ca2+ may be the general mechanism for initiating mitochondrial transfer. However, it is not clear how CD38 enzyme activity initiates the increase of cytoplasmic Ca2+ levels and further promotes mitochondrial transfer. It may be the increase in extracellular NAD+ (a substrate of CD38) caused by changes in the redox state of the cell.


Gap junction (GJ) proteins, especially connexin 43, have been confirmed to exist in TNTs. Connexin is very important for the Ca2+ propagation of neighboring cells through TNTs. GJ and TNTs are similar in composition, but GJ is different from TNTs in function. GJ can carry out short-range cell-to-cell interactions, allowing only 1.2 kDa molecular transfer, while TNTs mediate long-range cell-cell interactions, allowing greater material transfer. More research is needed to fully understand the contribution of GJ protein in TNT formation and mitochondrial transfer.

 

 


Mitochondrial metastasis in solid cancer

The current knowledge about mitochondrial metastasis in solid cancer is limited, and the results of various studies are often difficult to compare due to the use of different experimental systems (Table 1). Mesenchymal cells or fibroblasts are the most commonly used mitochondrial donors. However, tumor tissue is a complex environment composed of many different types of cells, and competition between cells may have an important impact on mitochondrial metastasis. In fact, in the co-culture of BMSCs, endothelial cells and MCF7 cells, the formation of TNTs between the three types of cells was observed, but mitochondria were only sent from endothelial cells to MCF7 cells. Recently, TNT-mediated mitochondrial transfer has also been found to occur between natural killer T cells and breast cancer cells. These studies indicate that the ability to donate mitochondria may be affected by specific cell types in the tumor microenvironment. Therefore, the results of mitochondrial transfer experiments using cells that are not normally present in the microenvironment of solid tumors (such as BMSCs or umbilical cord Wharton’s jelly cells) should be carefully interpreted.


Studies on the mechanism of mitochondrial transfer between solid tumor cells have shown that TNTs are the main route of delivery. The first mitochondrial metastasis occurred between mesenchymal cells with severely damaged or completely missing mitochondria and lung cancer cells. In order to promote mitochondrial transfer, many studies have used inhibitors such as rotenone to block electron transfer in the respiratory chain. Therefore, the OXPHOS state in the recipient cell seems to be a key factor in mediating mitochondrial transfer. However, no mitochondrial transfer occurred between BMSCs and osteosarcoma cells with pathogenic mtDNA mutations, which encode a key component of the OXPHOS system. In addition, studies have shown that BMSCs donate mitochondria to ovarian and breast cancer cells, lung adenocarcinoma cells and prostate cancer cells that have no obvious damage to mitochondria. This indicates that not only the state of mitochondria, but also specific metabolic requirements may play a role in promoting mitochondrial transfer.

 

 


Mitochondrial metastasis in hematological malignancies

The tumor microenvironment is also crucial to the progression and drug resistance of blood cancer. Obtaining new mitochondria from the bone marrow microenvironment is a way for leukemia cells to acquire drug resistance. So far, mitochondrial metastasis has been observed in various types of hematological malignancies, and mitochondrial metastasis appears to have tumor-promoting functions in these tumors.

 


Mitochondrial metastasis in acute lymphoblastic leukemia

The cross-communication between acute lymphoblastic leukemia (ALL) cells and their microenvironment proves that mitochondria are passed from MSCs to primary B cell precursor ALL cells through TNTs. The presence of TNTs promotes the transmission of signals from ALL cells to MSCs, affects the release of cytokines and chemokines in the microenvironment, and supports the survival of ALL cells and chemotherapy resistance. In addition to B cell ALL, mitochondrial transport of MSCs was later shown in T cell ALL (T-ALL). Mitochondrial transport is mediated by T-ALL cell/MSC adhesion and occurs through TNTs. However, unlike B-ALL cells, mitochondria are exported from malignant T-ALL cells to surrounding MSCs. This may be because T-ALL cells preferentially use glycolysis. This example can help reveal the signals and mechanisms that drive the directionality of transmission. Observe whether T-ALL cells can provide mitochondria for other types of cells, and whether the increase in the number of mitochondria in MSCs directly supports the tumor characteristics of T-ALL cells.

Mitochondrial transfer between cells in the tumor microenvironment
Table 1 Mitochondrial transfer studies

 

 

Mitochondrial metastasis in acute myeloid leukemia

Acute myeloid leukemia (AML) is a typical hematological malignancy that is highly dependent on OXPHOS. Compared with healthy CD34+ hematopoietic stem/progenitor cells or CD3+ lymphocytes, AML cells are more receptive to new mitochondria. When co-cultured with human BMSCs, AML cells can acquire additional mitochondria during the TNT-dependent process. However, another study found that endocytosis inhibitors blocked the mitochondrial exchange between mouse MS-5 BMSCs and human AML cells, indicating a TNT-independent transmission.


Commonly used chemotherapeutics such as cytarabine, etoposide and adriamycin can promote the uptake of mitochondria by AML cells. Therefore, by stimulating the oxidative metabolism of drug-resistant AML clones, this treatment may have a tumor-promoting effect. The surface molecule CD38 is another clinically relevant target of AML, which is essential for the transport of mitochondria from BMSCs to AML cells. Daratumumab is a monoclonal anti-CD38 antibody approved for the treatment of multiple myeloma (MM). Studies have shown that it can block the transport of mitochondria to AML cells under both in vitro and in vivo conditions and reduce oxygen consumption rate (OCR) , And inhibit the growth of leukemia cells. These studies indicate a novel and previously unexpected anti-tumor mechanism of anti-CD38 therapy.

 


Mitochondrial metastasis of multiple myeloma

Abnormal myeloma cells exist in the hypoxic environment of the bone marrow. Unexpectedly, primary multiple myeloma (MM) cells isolated from patient tissues have a higher basic OCR compared to multiple myeloma cell lines cultured in vitro for a long time. Similarly, when the established MM cell line was injected into mice or co-cultured with BMSCs, the production of OCR and ATP was significantly increased. The presence of BMSCs enhanced the mitochondrial metabolism and drug resistance of MM cells, suggesting that the bone marrow microenvironment may stimulate the aerobic respiration of MM cells. More in-depth studies have shown that TNT-mediated transfer of mitochondria from BMSCs to MM cells and ROS-inducing compounds, including commonly used protease inhibitors, significantly enhance this process.


CD38 plays a vital role in mitochondrial transfer and is currently one of the most attractive molecules in targeted therapy for MM patients. In xenograft models, treatment with anti-CD38 antibody or CD38 gene deletion can inhibit the mitochondrial transfer of BMSCs to MM cells and induce tumor shrinkage. The lower mitochondrial activity, especially the decline of OXPHOS, was previously thought to be related to the increased sensitivity of MM cells to protease inhibitors. Consistent with these observations, clinical data indicate that the combination therapy with anti-CD38 antibodies and protease inhibitors has a high efficacy. On the other hand, vascular cell adhesion molecule 1 (VCAM-1) is the main ligand of VLA-4 on MM cells. Proteasome inhibitors can inhibit the binding of BMSCs and MMs by down-regulating the expression of VCAM-1 on BMSCs. Causes mitochondrial transfer to be blocked.

 

 

Conclusion:

The potential targeting of direct transfer of mitochondria between cells provides huge opportunities for cancer treatment and tissue regeneration. The fact that mitochondrial metastasis appears to proceed in a similar manner in solid cancers and blood cancers further increases the importance of this process. It also emphasizes the importance of tumor microenvironment and cellular plasticity in tumor progression and drug resistance. In addition, the involvement of mitochondrial metastasis may provide an explanation for the unclear mechanism of action of some anticancer drugs. Future research on the molecular processes that control mitochondrial shuttling under normal and pathological conditions may bring many exciting discoveries and provide new therapeutic possibilities for improving tissue regeneration and cancer treatment.

 

 

Expert Comments:

We have introduced the metabolic communication of tumor microenvironment and the metabolism of mitochondria to provide targets for tumor treatment in the 197 and 198 issues of the public account. We recognize that mitochondria are the key metabolic driving factors for tumor growth.

Current clinical trials on mitochondrial metabolism There are also definite successes that make mitochondria become the forefront of tumor metabolism and immune metabolism research.

In the process of tumor progression and metastasis, the signal transmission between tumor cells and stromal cells plays an important role, and the study of mitochondrial metastasis can provide a new direction for our future tumor treatment.

 

The tumor microenvironment refers to the non-cancer cells and components present in the tumor, including the molecules they produce and release. The continuous interaction between tumor cells and tumor microenvironment plays a decisive role in tumor initiation, progression, metastasis and response to treatment. This review introduces the knowledge of mitochondrial transfer between cells, describes its relevance in the occurrence, development and drug resistance of cancer, summarizes the known molecules involved in mitochondrial sharing, and shows the mitochondria in solid tumors and hematological tumors Examples of exchange refer to studies on the specificity of tumor cell oxidative phosphorylation to inhibit tumor metastasis, the pathway of mitochondrial metastasis between cells, and the specificity of metastasis between solid tumors and hematological tumors.

Although the entire signaling mechanism that drives mitochondrial transfer is still unclear, the discovery of key molecules such as Miro1, Connexin43 and CD38 has opened the door to possible targeted therapies. The tumor microenvironment as a therapeutic target for tumors has aroused extensive research and clinical interest. The development and clinical trials of related drugs targeting the tumor microenvironment are already underway, and more new technologies and methods for interpreting the tumor microenvironment are also continuing. Exploring.

 

(source:internet, reference only)


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