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How can rapid growth cancer get nutrients in vivo?

How can rapid growth cancer get nutrients in vivo?


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When I was little, before I get into biological studying, I read a news talking about cancer would be totally cured after decades. I still remember that researchers had a theory to claim if they could limit the blood vessel generation near to tumor, then the rapidly growing cancer cell couldn't get enough nutrients and would kill them. However, this theory seems not to work well. Cancer cells or tumor still have another way to get enough nutrients to live, or at least, maintain themselves to survive and endanger the host. So, my question is how can rapid growth cancer get nutrients without blood vessels in vivo?


Long back in 1971 Falkman and others put forward new therapeutic implications of targeting blood vessels supplying nutrients to tumors. Treatment you are mentioning is called 'Anti-angiogenic therapy '. However current challenges in this therapy are resistance to antiangiogenic agents and non specificity. Plus there was huge 'normalization effect' which was actually helping other blood vessels around tumor. To answer your question, Cancer cell makes their own blood vessels instead relying on host machinery. There are many other factors also why this kind of treatment is not successful yet.


Metabolic reprogramming in cancer: starving tumors of essential nutrients to promote cell death

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How cancers get bigger

To start with, cancer cells stay inside the body tissue from which they have developed. For example, the lining of the bladder or the breast ducts. Doctors call this superficial cancer growth or carcinoma in situ (CIS).

The cancer cells grow and divide to create more cells and will eventually form a tumour. A tumour may contain millions of cancer cells.

All body tissues have a layer (a membrane) that keeps the cells of that tissue inside. This is the basement membrane. Cancer cells can break through this membrane. The cancer is called invasive cancer if it breaks through this membrane.


Microenvironmental autophagy promotes tumour growth

As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Extended Data Figure 1. NAA is induced…

Extended Data Figure 1. NAA is induced in the wing disc and ChAtg8a signal derives…

Extended Data Figure 2. Ras V12 scrib…

Extended Data Figure 2. Ras V12 scrib −/− tumours induce systemic autophagy in distal tissues…

Extended Data Figure 3. Generation and characterization…

Extended Data Figure 3. Generation and characterization of an atg14 allele

Extended Data Figure 4. Verification of reverse…

Extended Data Figure 4. Verification of reverse MARCM clonal technique for atg13 and atg14

Extended Data Figure 5. Local autophagy is…

Extended Data Figure 5. Local autophagy is required for tumour growth

Extended Data Figure 6. Inhibition of autophagy…

Extended Data Figure 6. Inhibition of autophagy reduces tumour proliferation, but does not increase cell…

Extended Data Figure 7. NAA responses

Extended Data Figure 7. NAA responses

Extended Data Figure 8. Transformed cells display…

Extended Data Figure 8. Transformed cells display increased mitochondrial mass, ROS, glucose uptake and reduced…

Extended Data Figure 9. Host autophagy requirement…

Extended Data Figure 9. Host autophagy requirement for tumour growth

Figure 1. Ras V12 scrib −/− tumours…

Figure 1. Ras V12 scrib −/− tumours induce NAA

Top, cartoon showing colour-coded larval tissues. ac…

Figure 2. Local NAA is required for…

Figure 2. Local NAA is required for tumour growth and invasion

Figure 3. Ras V12 scrib −/− tumours…

Figure 3. Ras V12 scrib −/− tumours produce ROS and induce NAA downstream of Egr/TNF,…

Figure 4. Malignant tumours are dependent on…

Figure 4. Malignant tumours are dependent on amino acid import and host autophagy


A Closer Look at the First Angiogenesis Inhibitors

The growth of blood vessels into tumors is only half of the story. It was postulated as long ago as 1971 by Dr. Judah Folkman that prevention of angiogenesis could inhibit tumor growth by starving them of vital nutrients.17 The existence of natural inhibitors of angiogenesis was hinted at by an intriguing observation made by surgeons. They found that the surgical removal of a large primary tumor often led to the rapid development of metastatic growths. This observation suggested that the primary tumor was producing something that kept small metastatic growths from progressing. When the large tumor was removed, the smaller tumors were free to grow.

The first naturally occuring inhibitor discovered was thrombospondin, identified in 1989 by Dr. Noel Bouck.18 Two more natural inhibitors were dicovered by Dr. Michael O'Reilly in Dr. Folkman's lab, angiostatin in 1994 and endostatin in 1997.19 20 Both molecules are small proteins that are derived from larger proteins that, remarkably, have different functions in the body.

As treatments, the first two inhibitors discovered shared two very exciting features: 1) Because they are natural products of the body, they should be much less toxic than conventional chemotherapy drugs. 2) Because they act on normal (blood vessel) cells instead of attacking the tumors directly, they should be much less likely to lead to the selection of drug-resistant tumors.

Angiostatin is no longer being examined as a possible cancer drug. Endostatin, in the form of Endostar® is in clinical trials.

Since blood vessel formation, or the lack of it, is at the root of many human diseases, controlling this process has potential in several disorders in addition to cancer. The story of Judah Folkman's search was the subject of a NOVA special that can be viewed online.

Since this process is key to the growth of tumors, many drugs are currently being investigated for their potential to inhibit angiogenesis and tumor growth and several drugs with antiangiogenesis activity have been approved to treat cancer.

Learn more about angiogenesis inhibitors in the cancer treatment section of the site.


Restricting a key cellular nutrient could slow tumor growth

This osteosarcoma cell appears with DNA in blue, mitochondria in yellow, and actin filaments in purple. Credit: Dylan Burnette and Jennifer Lippincott-Schwartz / Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Remove tumor cells from a living organism and place them in a dish, and they will multiply even faster than before. The mystery of why this is has long stumped cancer researchers, though many have simply focused on the mutations and chains of molecular reactions that could prompt such a disparity. Now, a group of MIT researchers suggests that the growth limitations in live organisms may stem from a different source: the cell's environment. More specifically, they found that the amino acid aspartate serves as a key nutrient needed for the "proliferation" or rapid duplication of cancer cells when oxygen is not freely available.

The biologists took cancer cells from various tissue types and engineered them to convert another, more abundant substrate into aspartate using the gene encoding an enzyme from guinea pigs. This had no effect on the cells sitting in a dish, but the same cells implanted into mice engendered tumors that grew faster than ever before. The researchers had increased the cells' aspartate supply, and in doing so successfully sped up proliferation in a living entity.

"There hasn't been a lot of thought into what slows tumor growth in terms of the cellular environment, including the sort of food cancer cells need," says Matthew Vander Heiden, associate professor of biology, associate director of the Koch Institute for Integrative Cancer Research, and senior author of the study. "For instance, if you're trying to get to a given destination and I want to slow you down, my best bet is to set up a roadblock at a place on your route where you'd experience a slow-down anyways, like a long traffic light. That's essentially what we're interested in here—understanding what nutrients the cell is already lacking that put the brakes on proliferation, and then further limiting those nutrients to inhibit growth even more."

Lucas Sullivan, a postdoc in Vander Heiden's lab, is the lead author of the study, which appeared in Nature Cell Biology on June 25.

Building the case for aspartate

Isolating a single factor that could impact tumor growth within an organism is tricky business. One potential candidate came to Sullivan via a paper he co-authored with graduate student Dan Gui in 2015, which asked a somewhat controversial question: Why is it that cells need to consume oxygen through cellular respiration in order to proliferate?

It's a rather counter-intuitive question, because some scientific literature suggests just the opposite: Cancer cells in an organism ("in vivo") do not enjoy the same access to oxygen as they would in a dish, and therefore don't depend on oxygen to produce enough energy to divide. Instead, they switch to a different process, fermentation, that doesn't require oxygen. But Sullivan and Gui noted that cancer cells do rely on oxygen for another reason: to produce aspartate as a byproduct.

Aspartate, they soon confirmed, does, in fact, play a crucial role in controlling the rate of cancer cell proliferation. In another study one year later, Sullivan and Gui noted that the antidiabetic drug metformin, known to inhibit mitochondria, slowed tumor growth and decreased aspartate levels in cells in vivo. Since mitochondria are key to cellular respiration, Sullivan reasoned that blocking their function in an already oxygen-constrained environment (the tumor) might make cancer cells vulnerable to further suppression of respiration—and aspartate—explaining why metformin seems to have such a strong effect on tumor growth.

Despite being potentially required for certain amino acids and the synthesis of all four DNA nucleotides, aspartate is already hard to come by, even in oxygen-rich environments. It's among the lowest concentration amino acids in our blood, and has no way to enter our cells unless a rare protein transporter is present. Precisely why aspartate import is so inefficient remains an evolutionary mystery one possibility is that its scarcity serves as a "failsafe," preventing cells from multiplying until they have all the resources to properly do so.

Regardless, the easiest way for cells to get aspartate is not to import it from outside, but rather to make it directly inside, breaking down another amino acid called asparagine to generate it. However, there are very few known mammals that have an enzyme capable of producing aspartate from asparagine—among them, the guinea pig.

Channeling the guinea pig

In the 1950s, a researcher named John Kidd made an accidental discovery. He injected cancer-ridden rats with sera from various animals—rabbits, horses, guinea pigs, and the like—and discovered that guinea pig serum alone shrunk the rats' tumors. It wasn't until years later that scientists learned it was an enzyme in the guinea pig blood called guinea pig asparaginase 1 (gpASNase1) that was responsible for this antitumorigenic effect. Today, we know about a host of simpler organisms with similar enzymes, including bacteria and zebrafish. In fact, bacterial asparaginase is approved as a medicine to treat acute lymphocytic leukemia.

Because guinea pigs are mammals and thus have similar metabolisms to our own, the MIT researchers decided to use gpASNase1 to increase aspartate levels in tumors in four different tumor types and ask whether the tumors would grow faster. This was the case for three of the four types: The colon cancer cells, osteosarcoma cells, and mouse pancreatic cancer cells divided more rapidly than before, but the human pancreatic cancer cells continued to proliferate at their normal pace.

"This is a relatively small sample, but you could take this to mean that not every cell in the body is as sensitive to loss of aspartate production as others," Sullivan says. "Acquiring aspartate may be a metabolic limitation for only a subset of cancers, since aspartate can be produced via a number of different pathways, not just through asparagine conversion."

When the researchers tried to slow tumor growth using the antidiabetic metformin, the cells expressing gpASNase1 remained unaffected—confirming Sullivan's prior suspicion that metformin slows tumor growth specifically by impeding cellular respiration and suppressing aspartate production.

"Our initial finding connecting metformin and proliferation was very serendipitous," he says, "but these most recent results are a clear proof of concept. They show that decreasing aspartate levels also decreases tumor growth, at least in some tumors. The next step is to determine if there are other ways to more intentionally target aspartate synthesis in certain tissues and improve our current therapeutic approaches."

Although the efficacy of using metformin to treat cancer remains controversial, these findings indicate that one means to target tumors would be to prevent them from accessing or producing nutrients like aspartate to make new cells.

"Although there are many limitations to cancer cell proliferation, which metabolites become limiting for tumor growth has been poorly understood," says Kivanc Birsoy, the Chapman-Perelman Assistant Professor at Rockefeller University. "This study identifies aspartate as one such limiting metabolite, and suggests that its availability could be targeted for anti-cancer therapies."

Birsoy is a former postdoc in professor of biology David Sabatini's lab, who authored a paper published in the same issue of Nature Cell Biology, identifying aspartate as a major growth limitation in oxygen-deprived tumors.

"These companion papers demonstrate that some tumors in vivo are really limited by the chemical processes that require oxygen to get the aspartate they need to grow, which can affect their sensitivity to drugs like metformin," Vander Heiden says. "We're beginning to realize that understanding which cancer patients will respond to which treatments may be determined by factors besides genetic mutations. To really get the full picture, we need to take into account where the tumor is located, its nutrient availability, and the environment in which it lives."


Lysosome functional status and cancer development and progression

As mentioned above, lysosomes participate in a variety of life activities in normal cells. Likewise, lysosomes play crucial roles in cancer development and progression (Table 1).

Lysosomes and cancer energy metabolism

Continuous proliferation requires a sufficient energy supply and raw materials for macromolecular synthesis. The uptake and decomposition of extracellular glycoproteins and glycolipids and the recycling of intracellular substances are pathways for cancer cells to obtain carbohydrates, lipids and amino acids [52]. The extracellular substances obtained by phagocytosis, endocytosis and macropinocytosis can be further delivered to lysosomes to generate nutrients through lysosomal degradation. Moreover, through autophagy, intracellular substances are degraded into the nutrients and energy required by cancer cells. Although the microenvironment of cancer cells is poor, another core function of lysosomes in cancer cells is to provide energy and metabolize precursors through the recycling of endogenous or exogenous macromolecules [53, 54]. In KRAS-driven lung cancer and pancreatic ductal adenocarcinoma cells, lysosomes can degrade substances that are recycled from the extracellular and intracellular environments to provide materials for cancer cell growth [55], and prevent AMP accumulation, energy crisis, and fatal nucleotide degradation [56]. As mentioned above, lysosomes play a key role in cellular nutrient sensing. Studies have found that some amino acids can be directly sensed and bound by molecules such as amino acid receptors and transporters in the plasma membrane and cytoplasm as signal molecules these amino acids can also be perceived by lysosomes [54]. mTORC1 is a highly conserved kinase complex in eukaryotic cells that can sense and integrate stimulation information such as energy and nutrient status to regulate cell growth and autophagy. When nutrients are lacking in cancer cells, MiT/TFE family of transcription factors can escape mTORC1-mediated negative regulation and locate in nucleus, thereby allowing cancer cells to maintain the activation of mTOR signaling and autophagy at the same time [57]. The activation of autophagy ensure efficient recycling of cellular material. This mechanism is associated with a variety of cancer metabolic activities. In cancers such as pancreatic ductal adenocarcinoma, renal cell carcinoma and non-small cell lung cancer, TFE3/TFEB and other transcription factors are activated to promote lysosomal biogenesis and functional activation, thereby maintaining steady-state metabolism in cancer cells and further promoting cancer malignancy [58,59,60]. This signal transduction mechanism not only upregulates lysosome biosynthesis but also increases autophagy to help cells cope with nutritional stress. The deletion of GATOR1 has been observed in human cancers and suggests that aberrant mTORC1 nutrient sensing plays a crucial role in cancers [25].

Lysosomes maintain cancer cell proliferation

Malignant cells must avoid oncogene-induced senescence (OIS) to achieve continuous proliferation [61]. The role of OIS in the inhibition of carcinogenesis is very important and involves gene expression at cell cycle checkpoints and activation of the aging-related secretory phenotype [62,63,64,65]. Interestingly, a large number of lysosome-specific phenotypes can be observed in senescent cells, including upregulated lysosomal gene expression and increased lysosome number/volume [66, 67]. The metabolic activity of senescent cells was originally thought to be lower than that of proliferating cells however, studies have shown that the metabolism of senescent cells is actually hyperactive and that the corresponding changes in lysosomes may provide a greater material basis for senescent cells [68,69,70,71]. During the OIS process, cellular oxidative metabolism increases, which is often associated with changes in chromatin structure, such as senescence-related heterochromatin. Heterochromatin foci can be extruded from the nucleus and enter the cytoplasm. Cancer cells degrade these cytoplasmic chromatin fragments by increasing the level of autophagy through increased lysosome synthesis, thereby maintaining the function of cancer cells and slowing aging [72]. Interestingly, the activation of proto-oncogenes or the absence of tumor suppressor genes can induce cell proliferation and induce changes in lysosome synthesis. In SV40-mediated immortalized transformed cells, molecular events such as MYC gene amplification and overexpression and KRAS mutant expression can increase the expression of lysosome catalase and glycosidase (including cathepsin D and cathepsin E) [73], suggesting that the expression of oncogenes can increase the number of lysosomes and enhance their functional state. In KrasG12D-driven lung tumor cell, the deletion of Atg5 or Atg7 reduces cell proliferation and tumor burden, suggesting that this is due to impaired autophagy. Atg7 deficiency can activate p53, which contributes to tumor suppression [74, 75]. Atg7 deficiency also reduces intiation, proliferation and development of melanoma, prostate cancer and colorectal cancer [76,77,78]. FIP200 is an essential autophagy protein to initiate autophagosome formation and the ablation of FIP200 can diminish the tumor-initiating properties of breast cancer stem cells [79]. Lysosomal calcium homeostasis can affect tumor proliferation. TRPML-2 knockdown can inhibit cell viability and proliferation, affect the cell cycle, promote apoptotic cell death in glioma cell lines. The mRNA and protein levels of TRPML-2 have been shown to increase with pathological grade [80]. The above results indicate that during the process of unregulated cancer cell proliferation, lysosomes exhibit increased biosynthesis and an enhanced functional status, which promotes intracellular substance circulation and the degradation of harmful intracellular byproducts, thereby maintaining cancer cell proliferation.

Lysosomes promote cancer invasion and metastasis

Invasion and metastasis are the most prominent biological characteristics of malignant cancers and are also the leading causes of death among patients. Epithelial–mesenchymal transition (EMT) plays a critical role in cancer metastasis by enabling epithelial cells to acquire motility and invasiveness, which are characteristic of mesenchymal cells [81]. Autophagy plays an important role in cancer invasion and metastasis. Studies have found that autophagy is activated under adverse conditions, such as hypoxia and the accumulation of acidic metabolic products. Cells can use autophagy to degrade epithelial-derived molecules such as E-cadherin to induce EMT, thereby enhancing cancer cell invasiveness and metastasis [82, 83]. In vitro, EMT-inducing factors can downregulate the expression of E-cadherin on the plasma membrane of cancer cells by promoting the degradation of E-cadherin in lysosomes and inhibiting recycling, which suggests that the lysosomal degradation pathway promotes invasion and metastasis [84]. In addition, some metastasis suppressors, such as NM23-H1, can promote breast cancer invasion through lysosomal degradation [85]. Autophagy also supports cancer invasion and metastasis by promoting disassembly of cell–matrix FAs. This process was mediated by the interaction of processed LC3 with paxillin, a key FA component [86]. Autophagy-dependent secretion of the proinvasive cytokine, such as IL6, also promotes cancer invasion [87].

Degradation and modification of the ECM are necessary conditions for cancer invasion and metastasis [88, 89]. The release of lysosomal hydrolases, such as cathepsin, plays an important role in this process. TRPMLs and TPCs can affect the functional status of lysosomes and promote tumor invasion and metastasis by regulating lysosomal calcium homeostasis [14]. TRPML1-mediated lysosomal calcium release can promote TFEB nuclear translocation and increase lysosome biogenesis and autophagy. The activation of TPCs also promotes TFEB nuclear translocation. In the human hepatocellular carcinoma cell line HepG2, tetrabromobisphenol A (TBBPA) activates TRPML1, which promotes the release of lysosomal calcium and the nuclear translocation of TFEB and increases lysosomal exocytosis. Cancer cells then secrete cathepsins through lysosomal exocytosis [15]. Cathepsin can act directly or through the activation of matrix metalloproteinases (MMPs) to degrade and remodel the ECM, thus enhancing the invasion and metastasis of cancer cells. A study on a mouse model of pancreatic cancer found that the absence of cathepsin B reduced the probability of liver metastasis and prolonged the survival time of cancer-bearing mice [90]. Cathepsins B, S, and E are all involved in invasion and metastasis in various cancers [91,92,93]. Silencing TPC1 and TPC2 can reduce the adhesion and migration of invasive tumor cells. The inhibition of TPCs leads to the accumulation of integrins in endocytic vesicles and to impaired formation of leading edges. Alternatively, the inhibition of TRPMLs or TPCs may affect EGFR recycling and possibly delay or prevent cancer cell migration and/or proliferation [94, 95]. In addition, studies have confirmed that various lysosomal proteins, such as lysosome-associated protein-1 (LAMP1) [96, 97], LAMP3 [98, 99] and LAPTM4BP [100], are highly expressed in many malignant cancers, including melanoma, lung cancer, breast cancer and liver cancer, and that such high expression is associated with invasion and metastasis. LAMP-1 is abundant on the cell surface of highly metastatic cancer cells, especially metastatic colon cancer cells, which suggests that lysosomal proteins are important in cell adhesion and migration [101]. Researchers have examined the sensitivity of bladder cancer cell lines with different invasive potentials to the lysosomal inhibitors chloroquine (Cq) and bafilomycin and found that highly invasive bladder cancer cells were more sensitive to Cq and bafilomycin, while the invasive ability of Cq-resistant cells selected by screening highly invasive cells was significantly decreased [102]. These results suggest that lysosomes can be used as potential therapeutic targets in metastatic cancers.

Lysosomes promote cancer angiogenesis

Angiogenesis has an important impact on cancer growth, invasion and metastasis. Remodeling of the ECM and vascular basement membrane is essential for initiating angiogenesis and vascular sprouting [103, 104]. The lytic granules cleaved by lysosomal exocytosis can destroy vascular basement membrane components at physiological pH [105]. Studies have shown that cathepsins D, B, S, K and L all play roles in promoting angiogenesis. On the one hand, activation of MMPs by cathepsin can mimic angiogenesis on the other hand, cathepsin can directly act as a cytokine to stimulate the proliferation of vascular endothelial cells, thereby playing a role in promoting angiogenesis [106]. In addition, under anoxic conditions, cathepsin K can play important roles in angiogenesis through the activation of Notch homolog 1, translocation-associated (NOTCH1) signaling. Cathepsin K knockdown in endothelial cells results in reduced angiogenesis [107]. In addition, lysosomes also play a role in endothelial cell migration factor regulation. Rab GTPase is essential for angiogenesis and participates in the endosomal recycling of vascular endothelial growth factor receptor 2 (VEGFR2) [108]. Genetic deletion of Rab4a and Rab11a and the inhibition of lysosome activity by chloroquine can lead to defects in VCl2 lysosomal-plasma membrane recycling and inhibition of endothelial cell migration [108]. Lysosomal calcium homeostasis is associated with angiogenesis. The blockade of TPCs can inhibit VEGF-induced neoangiogenesis, which is mediated by TPC2-dependent calcium signaling. The inhibition of signaling pathways involving VEGFR2, NAADP, TPC2, and Ca2+ release from acidic stores can greatly reduce the activation of VEGFR2 downstream targets, which would then block angiogenesis, in both in vitro and in vivo models [109]. In-depth studies on the internal mechanisms and key molecules of lysosomal-regulated angiogenesis are currently lacking. Further studies on the specific roles of lysosomes in cancer angiogenesis may lead to the development of new anti-angiogenesis therapeutic strategies.

Lysosomes and cancer immunity

In recent years, the great success of immune checkpoint therapy has confirmed the role of the immune system in cancer treatment [110]. It has been shown that lysosomes can serve as a major destruction location for immune checkpoint molecules, as secretory lysosomes can temporarily store immune checkpoint proteins, such as CTLA-4, PD-L1, TIM-3, CD70, CD200, and CD47 [111]. Studies have shown that CTLA-4 is a transmembrane T cell inhibitory protein mainly located in the plasma membrane and cytoplasm however, attachment to the plasma membrane is important for CTLA-4 to perform its functions [112]. CTLA-4 expression is largely regulated by lysosomes. On the one hand, lysosomes degrade CTLA-4 on the other hand, lysosomes are responsible for CTLA-4 transport to the plasma membrane. CTLA-4 can bind to activator protein 1 (AP1) and AP2 [113, 114] to promote its transport to lysosomes for degradation. In addition, CTLA-4 can enter the cytoplasm for lysosomal degradation via endocytosis [115, 116]. Lysosomes containing CTLA-4 can be transferred to the T cell receptor (TCR), which subsequently secretes CTLA-4, increasing cell surface CTLA-4. After tyrosine phosphorylation, CTLA-4 remains on the cell surface [117, 118]. Therefore, the expression of other inhibitory receptors in T cells (e.g., PD-1) can be confidently assumed to also be similarly regulated by lysosomes however, the role of lysosomes in this process is still unclear.

Secretory lysosomes, also known as lytic granules, contain proapoptotic granzymes and perforin and can also participate in the regulation of immune cell functions. Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) play a crucial role in immunity, as they are responsible for the elimination of both virally infected and tumorigenic cells. The clearance of target cells is dependent on the regulated exocytosis of secretory lysosomes, which can deliver proapoptotic granzymes and perforin to target cells [119]. Upon recognition of target cells, microtubules and actin filaments in CTLs are reorganized, which results in the polarization of the centrosome towards the immunological synapse (IS), which are formed with the target cells. Rab7 can interact with Rab7-interacting lysosomal protein (RILP) to recruit dynein to secretory lysosomes, which mediate minus-end-directed movement of secretory lysosomes to IS. Then, the contents in secretory lysosomes can be released, which leads to the destroy of target cells [120]. However, cancer cell autophagy may serve to intercept granzymes and perforin released by cytotoxic immune cells, blunting the efficacy of anti-tumor immune response [121, 122]. Impaired autophagy in breast cancer cells activates the immune response, IFN production and lymphocyte infiltration [79].

TRPMLs also play an important role in immunity [123]. When macrophages bind particles, the TRPML1 channel in lysosomes becomes activated and mediates Ca2+ release from lysosomes, which induces lysosomal exocytosis at the site of the phagocytic cup this in turn increases the surface area of the phagocytosing macrophage and promotes the engulfment of large particles. TRPML1-mediated Ca2+ release is indispensable for phagosome maturation [124]. Macrophages can produce and secrete a variety of cytokines and chemokines after stimulation. Tumor-associated macrophages can be stimulated by IL-4, IL-10, or IL-13 and then migrate into tumor tissue, where they perform protumorigenic functions [125]. Recent findings have shown that the TRPML2 channel plays a crucial role in the release of chemokines as well as in the stimulation of macrophage migration [126, 127]. NK cell activity is regulated by the dynamic balance between activating and inhibitory signals, which determine whether NK cells kill the target cell. Major histocompatibility complex (MHC) class I molecules can be recognized by inhibitory receptors. The expression of MHC class I on virus-infected cells and tumor cells is decreased, which will be recognized by NK cells and promote the killing of these cells by NK cells. A process termed NK cell education describes the interaction between self-MHC and inhibitory receptors on NK cells, which calibrates NK cell effector capacities. TRPML1 participates in this process by regulating secretory lysosomes, granzyme B content, and the effector function of NK cells [128].

In summary, lysosomes in cancer cells are involved in various biological events affecting the development and progression of cancers. This finding provides useful clues for the diagnosis and treatment of cancers. Identification of the specific functions of lysosomes can help predict the prognosis of cancer patients and formulate individualized treatments. The functional status of lysosomes is closely related to their intracellular distribution. Understanding and exploring the lysosome distribution in cancer cells and the effects of different distributions on the development and progression of cancers can provide more comprehensive lysosome information and thus a theoretical basis for further individualized diagnosis and treatment strategies for cancer.


Chapter 17 - The Biology of Nutrients : Genetic and Molecular Principles*

The intake of nutrients for growth, repair, and energy is an age-old, intuitive concept of nutrition regarding the role of nutrients in the body. Unlike treating diseases with drug interventions, treating adverse nutritional consequences (e.g., obesity) with nutritional intervention has remained elusive. This is, at least in part, due to the acute nature of the adverse effects of disease as opposed to the chronic nature of the adverse effects of inappropriate nutritional practices. Advances in genomic technologies have made the concept of individualized nutrition an achievable goal just like the concept of individualized medicine. The fine-tuning of nutritional intervention will require a thorough understanding of nutrient-mediated effects at the molecular level.


How cancer cells get by on a starvation diet

Cancer cells usually live in an environment with limited supplies of the nutrients they need to proliferate — most notably, oxygen and glucose. However, they are still able to divide uncontrollably, producing new cancer cells.

A new study from researchers at MIT and the Massachusetts General Hospital (MGH) Cancer Center helps to explain how this is possible. The researchers found that when deprived of oxygen, cancer cells (and many other mammalian cells) can engage an alternate metabolic pathway that allows them to use glutamine, a plentiful amino acid, as the starting material for synthesizing fatty molecules known as lipids. These lipids are essential components of many cell structures, including cell membranes.

The finding, reported in the Nov. 20 online edition of Nature, challenges the long-held belief that cells synthesize most of their lipids from glucose, and raises the possibility of developing drugs that starve tumor cells by cutting off this alternate pathway.

Lead author of the paper is Christian Metallo, a former postdoc in the lab of Gregory Stephanopoulos, the William Henry Dow Professor of Chemical Engineering and Biotechnology at MIT and a corresponding author of the paper. Othon Iliopoulos, an assistant professor of medicine at Harvard Medical School and MGH, is the paper’s other corresponding author.

Alternate pathways

Much of the body’s supply of oxygen and glucose is carried in the bloodstream, but blood vessels often do not penetrate far into the body of tumors, so most cancer cells are deficient in those nutrients. This means they can’t produce fatty acids using the normal lipid-synthesis pathway that depends mostly on glucose.

In prior work, Stephanopoulos’ lab identified a metabolic pathway that uses glutamine instead of glucose to produce lipids the new paper shows that this alternate pathway is much more commonly used than originally thought. The researchers found that in both normal and cancerous cells, lack of oxygen — a state known as hypoxia — provokes a switch to the alternate pathway.

In a normal oxygen environment, 80 percent of a cell’s new lipids come from glucose, and 20 percent from glutamine. That ratio is reversed in a hypoxic environment, Stephanopoulos says.

“We saw, for the first time, cancer cells using substrates other than glucose to produce lipids, which they need very much for their rapid growth,” Iliopoulos explains. “This is the first step to answering the question of how new cell mass is synthesized during hypoxia, which is a hallmark of human malignancies.”

The glutamine may come from within the cell or from neighboring cells, or the extracellular fluid that surrounds cells.

“There’s protein everywhere,” says Matthew Vander Heiden, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology at MIT and a co-author of the Nature paper. “The new pathway allows cells to conserve what glucose they do have, perhaps to make RNA and DNA, and then co-opt the new pathway to make lipids so they can grow under low oxygen.”

The switch from glucose to glutamine is triggered by low oxygen and allows cancer cells to thrive and proliferate in an environment with minimal glucose, though it is not clear how this is done. “Elucidating the molecular mechanism regulating this switch would be important in understanding regulation of cancer metabolism,” Stephanopoulos says. “This could be important not only for cancer cells but also other cells growing in hypoxic environments, such as stem cells, placenta and during embryonic development.”

New insights into old models

The researchers are now looking into what other unexpected sources might be diverted into lipid-synthesis pathways under low oxygen. “We had to revise models of metabolism that had been established over the past 50 years. This opens up the possibility for more exciting discoveries in this field that may impact strategies of therapy,” Metallo says.

A better understanding of metabolic pathways and their regulation raises the possibility of developing new drugs that could selectively disrupt key metabolic pathways for cancer cell survival and growth. One possible target is the enzyme isocitrate dehydrogenase, which performs a critical step in the transformation of glutamine to acetyl CoA, a lipid precursor.

“While this target is not new, our findings point to a new function and, hence, generate new ideas for drug development,” Iliopoulos says. “The better we understand the molecular basis of these phenomena, the more optimistic we can be about efforts to translate these basic results into effective treatments of cancer.”

“We’ve been looking, as a field, for almost 90 years for a metabolic pathway that could truly be used to differentiate malignant tumors from normal tissues,” says Ralph DeBerardinis, an assistant professor of pediatrics and genetics at the University of Texas Southwestern Medical Center, who was not involved in this research. He adds that more study is needed, but “if this could be exploited, that could have significant therapeutic potential.”


A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov 7(11) 1266-83. ©2017 AACR.See related commentary by Towers and Thorburn, p. 1218This article is highlighted in the In This Issue feature, p. 1201.

©2017 American Association for Cancer Research.

Conflict of interest statement

Conflict of Interest Statement: RA and JW are inventors on 3 patent applications related to this work. One patent has been licensed to a biotech company to promote clinical development of Lys05 derivatives.

Figures

Figure 1. DQs have superior anti-cancer efficacy…

Figure 1. DQs have superior anti-cancer efficacy amongst dimeric anti-malarials

Figure 2. Central nitrogen methylation status directs…

Figure 2. Central nitrogen methylation status directs effects upon autophagy, induction versus inhibition

Figure 3. Central nitrogen methylation status dictates…

Figure 3. Central nitrogen methylation status dictates DNA damage versus lysosomal membrane permeability

Figure 4. PPT1 is a target of…

Figure 4. PPT1 is a target of DQ661

Figure 5. DQ661 functionally inhibits mTORC1

Figure 5. DQ661 functionally inhibits mTORC1

Figure 6. DQ661 has significant single-agent in…

Figure 6. DQ661 has significant single-agent in vivo activity in melanoma xenograft model

Figure 7. DQ661 improves survival in colon…

Figure 7. DQ661 improves survival in colon cancer model and potentiates activity of gemcitabine in…