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Cancer in cardiac cells

Cancer in cardiac cells


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We were recently taught that cancer occurs only in those cells which undergo cell division so, cancer is not possible in cardiac cells and neurons. But we know that till a certain age our heart grows in size so that means it goes under cell division. So doesn't that mean that cancer can also occur in heart cells?


Though very rare, primary cardiac tumours do exist.

Most of the 1° cardiac tumours are benign, malignancy occurence is pretty much low.

Give it a read- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113129/


As the other answer has already stated, there are cases of heart cancer. Just to expand on that answer further, according to this article, the rate of heart tumors is a mere 1.38 in 100,000 people per year and of that only around 10% are malignant (truly cancerous tumors) in nature. Just to put this into perspective of how low of a rate this is, the overall rate of cancer in the U.S. for both men and women combined is 352.2 per 100,000.[source]

Doing some rudimentary calculations, if the rate of malignant tumors is one tenth of 1.38 in 100,000, that means the rate of heart cancer is around 0.14 per 100,000! Just to add to how rare this is, the Mayo Clinic on average only sees around one case of heart cancer per year.[source]

Also, to clarify your statement about what types of cells can have cancer, it is not only dividing cells that can have cancer (even though the majority of cancer originates from cells undergoing a lot of cell division such as the skin and GI tract). While cell division by its nature causes a vast number of the mutations which would potentially lead to cancer, other environmental factors such as toxins and radiation could cause also cause similar mutations in cells that might not even be dividing.


Cardiomyocytes(Cardiac Muscle Cells)

Also known as myocardiocytes, cardiomyocytes are cells that make up the heart muscle/cardiac muscle.

As the chief cell type of the heart, cardiac cells are primarily involved in the contractile function of the heart that enables the pumping of blood around the body. In human beings, as well as many other animals, cardiomyocytes are the first cells to terminally differentiate thus making the heart one of the first organs to form in a developing fetus.

In the embryo of a mouse, for instance, precursor cells of the cardiac muscles have been shown to start developing about 6 days after fertilization. Although cardiomyocytes contain many of the organelles found in other animal cells, they also contain others (e.g. myofibrils) that allow them to effectively perform their function.

Some of the main characteristics include:

  • Are elongated cylindrical cells and striated
  • A majority of cardiomyocytes have a single nucleus
  • Have contractile proteins
  • Cardiomyocytes are attached to each other through intercalated discs

Why cancer cells waste so much energy

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In the 1920s, German chemist Otto Warburg discovered that cancer cells don’t metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient.

MIT biologists have now found a possible answer to this longstanding question. In a study appearing in Molecular Cell, they showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

“This has really been a hundred-year-old paradox that many people have tried to explain in different ways,” says Matthew Vander Heiden, an associate professor of biology at MIT and associate director of MIT’s Koch Institute for Integrative Cancer Research. “What we found is that under certain circumstances, cells need to do more of these electron transfer reactions, which require NAD+, in order to make molecules such as DNA.”

Vander Heiden is the senior author of the new study, and the lead authors are former MIT graduate student and postdoc Alba Luengo PhD ’18 and graduate student Zhaoqi Li.

Inefficient metabolism

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don’t have enough oxygen available to perform aerobic respiration.

Since Warburg’s discovery, scientists have put forth many theories for why cancer cells switch to the inefficient fermentation pathway. Warburg originally proposed that cancer cells’ mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

In this study, the MIT team decided to try to come up with a solution by asking what would happen if they suppressed cancer cells’ ability to perform fermentation. To do that, they treated the cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway.

They saw, as others have previously shown, that blocking fermentation slows down cancer cells’ growth. Then, they tried to figure out how to restore the cells’ ability to proliferate, while still blocking fermentation. One approach they tried was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins.

When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn’t perform fermentation. This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows.

“We hypothesized that when you make both NAD+ and ATP together, if you can't get rid of ATP, it's going to back up the whole system such that you also cannot make NAD+,” Li says.

Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. “If you step back and look at the pathways, what you realize is that fermentation allows you to generate NAD+ in an uncoupled way,” Luengo says.

Solving the paradox

The researchers tested this idea in other types of rapidly proliferating cells, including immune cells, and found that blocking fermentation but allowing alternative methods of NAD+ production enabled cells to continue rapidly dividing. They also observed the same phenomenon in nonmammalian cells such as yeast, which perform a different type of fermentation that produces ethanol.

“Not all proliferating cells have to do this,” Vander Heiden says. “It’s really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they’re burning, that’s when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed.”

The findings suggest that drugs that force cancer cells to switch back to aerobic respiration instead of fermentation could offer a possible way to treat tumors. Drugs that inhibit NAD+ production could also have a beneficial effect, the researchers say.

The research was funded by the Ludwig Center for Molecular Oncology, the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Medical Research Council, NHS Blood and Transplant, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, Stand Up 2 Cancer, the Lustgarten Foundation, and the MIT Center for Precision Cancer Medicine.


Cancer Metastasis

Leah Cook, PhD
My lab’s research is focused on the role of the tumor microenvironment in cancer progression and metastasis. Prostate cancer metastasizes to bone more frequently than any other tissue site metastatic progression to bone is associated with poor survival outcomes of prostate cancer.  Within bone, metastatic cancer cells highjack the normal couple process of bone remodeling, resulting in excess bone degradation and subsequent release of growth factors that promote tumor growth (see figure). Additionally, cancer cells progress and mediate bone turnover through molecular and cellular interactions with the surrounding bone stroma. A major focus of the lab involves investigation of cellular interactions within the prostate tumor bone microenvironment that contribute to tumor progression and cancer-induced bone disease.  We are currently focusing on identifying the importance of innate immune cells and bone stromal cells in prostate cancer progression and cancer-induced bone disease. Another focus of my lab is to define the importance of innate immune cells in metastatic progression and chemoresistance of pancreatic cancer. We are using a combination of transcriptome and proteomic profiling of patient samples and mouse in vivo models of cancer metastasis along with development of computational models to test putative targets. My goal is to identify novel immunotherapeutic targets for treating and curing metastatic cancers.  Dr. Cook's research is also listed under Innate Immunity.

Rakesh K. Singh, PhD
The overall goal of our research is to define the mechanism(s) that regulate the process of metastasis. We hypothesize that metastasis is a highly selective process that is regulated by interrelated mechanisms whose outcome is dependent upon both the intrinsic properties of tumor cells and the host response. Using human tumors xenografted in nude mice and murine tumor models, these studies have demonstrated the role of host-derived factors in regulating angiogenesis, resulting in site-specific expression of angiogenic factors, including basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and metastasis. Further characterization of the cellular and molecular mechanisms underlying these processes are currently ongoing in our laboratory. In addition, we are investigating the mechanism(s) of organ-specific metastasis. Recent reports suggest specific organ tissues carry unique marker molecules accessible to circulating cells. We have identified the molecule(s) expressed in organ tissues, which might be important to organ-specific metastasis using phage display libraries. Further characterization of organ-specific signature molecules will be useful in designing novel, highly targeted therapeutic approaches against organ-specific metastasis. In addition, our current research activities have also been focused on designing the strategies for inhibiting tumor-induced angiogenesis and activating anti-tumor immunity with the potential for synergizing the outcome of conventional therapeutic approaches, as well as understanding the role of tumor-stromal interaction in tumor progression and metastasis.

James Talmadge, PhD
Basic/translational research studies are focused on host-tumor interactions during tumor progression, metastasis and cytoreductive therapy. We have focused on the effect of mammary tumor growth on the expansion and trafficking of MDSCs, and strategies to control proliferation and function, including molecular therapeutics.  Our current focus is on dietary regulation in a collaboration with Drs. John G. Sharp, Genetics Cell Biology & Anatomy Geoffrey Thiele, Internal Medicine Timothy R. McGuire, Pharmacy Leah Cook, Pathology/Microbiology Paul Black, Dept. of Biochemistry UNL and Concetta C. DiRusso, Dept. of Nutrition UNL.  This collaboration builds on the observation that omega 3 and omega 6 poly unsaturated fatty acids (PUFA) regulate inflammation.  Our studies have uniquely separated obesity from dietary PUFA using isocaloric and isolipidic diets.  Our original studies reported PUFA regulation of hepatic and mammary gland histopathology that has been extended to assess the impact of dietary PUFA regulation of mammary tumor growth and metastasis.  Perhaps the most exciting observation is the impact of omega 6 PUFA on accelerating tumor induction, growth and metastasis, including sites of metastasis that are depressed by omega 3 PUFA intervention.  Dietary omega 6 PUFA not only increases pulmonary and hepatic metastases but also results in cardiac, contralateral mammary gland, ovarian and bone metastases (Figure 2).  The latter is 

notable, as our metastasis model of orthrotropic primary tumors and spontaneous metastases to bone is unique, providing an ideal approach to study osseous metastasis.  The overwhelming majority of bone metastasis studies uses models of artificial bone metastasis, via left ventricle injection or direct injection into or onto bones.  Thus, in contrast to these approaches, our experimental approach incorporates all of the steps in the process of metastasis.  The impetus for the studies into bone metastasis came from the observation of postural paralysis in tumor bearing mice on the omega 6 diets.  In addition to Our studies to date have included gross, histologic and quantitative immunohistochemistry (IHC) analysis targeting neutrophils, macrophages, and T-cells, as well as proliferation and apoptosis.  Mechanistic analysis has come from metabolomic, qRT-PCR and Western blots providing insight, not only in metastasis including osseous metastasis, but also prevention and interventional studies for neoplasia.histopathologic and immunohistochemical analysis, we have undertaken micro CT analysis that has revealed extensive decalcification (Figure 3).  In association with the decalcification, we have observed spontaneous fractures (resulting in posterior paralysis) and callus formation. Dr. Talmadge's research is also listed under Transplantation Immunology.


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Doubled-up detection

Such models can provide a more complete picture of how tumour cells grow and change. But they also require new computational algorithms. Models that have conventionally been used to infer phylogenetic relationships between cells can’t handle the large amounts of information generated when a lineage-tracing data set is combined with one from single-cell RNA sequencing.

It’s a problem that developmental biologists have long struggled with, says geneticist Jay Shendure at the University of Washington in Seattle, whose group developed one of the first CRISPR systems for simultaneous lineage tracing and RNA sequencing 7 .

When it comes to lineage tracing in cancer studies, the biggest problems are technical: recovering sufficient amounts of barcode and handling missing data. Lineage-tracing studies often have gaps, because some cell populations disappear or the amounts of barcode sequence in a sample are too small to process. Algorithms can struggle to handle these gaps, Shendure says, so it’s crucial to maximize the yield and stability of the RNA sequence that encodes the barcode. “You need relatively high rates of recovery,” he says. “If you put x cells into a protocol, you want to get a relatively high fraction of them back.”

In a study published this year 8 , UCSF cancer researcher Trever Bivona and his colleagues simultaneously tracked lineages and changes in RNA expression in lung cancer cells that had been transplanted into animals. Their Cas9-based tool enabled them to follow, in real time, how genetic changes drove cancer cells to seed tumours in distant tissues — the process of metastasis.

The team captured lineage and gene-expression data for more than 40,000 mouse cells from 6 different locations in animals’ bodies, and found that cells moved back and forth between various genetic states several times before committing to a distinct, differentiated path.

To analyse these voluminous data, Bivona’s collaborators — biologist Jonathan Weissman at the Whitehead Institute in Cambridge, Massachusetts, and computer scientist Nir Yosef at the University of California, Berkeley — developed a suite of tools called Cassiopeia, which helps to reconstruct lineages on the basis of CRISPR–Cas9 barcode data 9 . They and others have made their analytical tools freely available to other researchers (see go.nature.com/2ptezwd).

For her part, Bhaduri frequently turns to a toolset named Seurat 10 , developed by statistician Rahul Satija and computational biologist Aviv Regev when they were at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts. The Seurat tools allow Bhaduri to simultaneously analyse changes in gene expression and variations in the number of copies of a particular gene in single cells.

Whatever toolset researchers choose, Bhaduri recommends that people who are new to such analyses rely on tutorials and work through courses provided by algorithm developers. Those who have developed their own in-house analytical software, such as Vermeulen and others, typically collaborate with biostatisticians to do so.

Still, better tools are needed, Shendure says. “As the number of cells in a phylogenetic tree grows, the number of possible arrangements increases exponentially,” he says. “We’re going to need richer tools before we can fully realize the potential of this line of inquiry.”


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Conclusions

In conclusion, our results indicate that oxidative stresses (AA, H2O2, CoCl2 and H/R) dramatically increased the expression of miR-711 in heart cells. Over-expression of miR-711 increased cell apoptosis/death and mitochondrial damage in response to oxidative stress. miR-711 negatively regulates Ang-1, FGF14 and Cacna1c in response to AA and H/R. Both HIF-1α and NFКB regulate miR-711 expression under oxidative stress in H9c2 cells. miR-711 might be a potential new target in the prevention of damage induced by oxidative stress and I/R injury.


Identification of novel dynamin-related protein 1 (Drp1) GTPase inhibitors: Therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia-reperfusion injury

Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemia-reperfusion injury (IR). Mitochondrial fission is mainly mediated by dynamin-related protein 1 (Drp1), a large GTPase. The GTPase activity of Drp1 is essential for its fissogenic activity. Therefore, we aimed to identify Drp1 inhibitors and evaluate their anti-neoplastic and cardioprotective properties in five cancer cell lines (A549, SK-MES-1, SK-LU-1, SW 900, and MCF7) and an experimental cardiac IR injury model. Virtual screening of a chemical library revealed 17 compounds with high predicted affinity to the GTPase domain of Drp1. In silico screening identified an ellipticine compound, Drpitor1, as a putative, potent Drp1 inhibitor. We also synthesized a congener of Drpitor1 to remove the methoxymethyl group and reduce hydrolytic lability (Drpitor1a). Drpitor1 and Drpitor1a inhibited the GTPase activity of Drp1 without inhibiting the GTPase of dynamin 1. Drpitor1 and Drpitor1a have greater potency than the current standard Drp1 GTPase inhibitor, mdivi-1, (IC50 for mitochondrial fragmentation are 0.09, 0.06, and 10 μM, respectively). Both Drpitors reduced proliferation and induced apoptosis in cancer cells. Drpitor1a suppressed lung cancer tumor growth in a mouse xenograft model. Drpitor1a also inhibited mitochondrial ROS production, prevented mitochondrial fission, and improved right ventricular diastolic dysfunction during IR injury. In conclusion, Drpitors are useful tools for understanding mitochondrial dynamics and have therapeutic potential in treating cancer and cardiac IR injury.

Keywords: breast cancer ellipticine lung cancer mitochondrial division inhibitor 1 (mdivi‐1) mitochondrial dynamics mitochondrial fission right ventricle.


American Association for Cancer Research honors stem cell biology expert

American Association for Cancer Research has recognized Hans Clevers, MD, PhD, FAACR, with the 2021 Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research.

The award honors Clevers for his contributions to regenerative cancer medicine, according to an AACR press release.

Source: Adobe Stock.

Clevers&rsquo research led to the development of organoids, which have applications in multiple avenues of research, including regenerative cancer medicine and testing of novel anticancer therapeutics, the release stated. His studies of the Wnt signaling pathway &mdash mutations in which can contribute to development and progression of colon cancer &mdash has propelled research efforts that target the pathway with novel therapeutics, according to the release.

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&ldquoWe are extremely proud to honor Dr. Clevers with this year&rsquos Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research,&rdquo Margaret Foti, PhD, MD (hc), CEO of AACR, said in the release. &ldquoHis pioneering research in stem cell biology, which led to the establishment of organoids as an essential model system for cancer research, has deepened our understanding of cancer&rsquos origins and revolutionized cancer drug development for the benefit of patients around the world.&rdquo

Clevers is a professor of molecular genetics at University Medical Center in Utrecht, Netherlands, where he serves as principal investigator at Hubrecht Institute for Developmental Biology and Stem Cell Research and at Princess Máxima Center for Pediatric Oncology.

He will be presented with the award during the virtual AACR Annual Meeting, scheduled for April 10-15 and May 17-21.


Cytoskeleton

The cytoskeleton is an intricate network of proteins that criss-cross the cytoplasm of cells. The cytoskeleton is composed of a wide variety of proteins. These proteins often form long twisted strands that look like electrical wire or the cables used to hold up bridges. Like these man-made components, the proteins that make up the cytoskeleton are both strong and flexible.

A main fiber type, actin, is made up of long strings (polymers) of the protein actin. The image below shows the actin fibers in a cow endothelial (blood vessel) cell. The yellow colored strings are the polymerized form of the protein and the red color indicates the presence of the single protein units.

Another critical cytoskeletal fiber is the microtubules. They are also polymers, and are comprised of the protein tubulin. The image below shows the microtubules in a cow endothelial cell.

As can be seen from the images above, the cytoskeleton is distributed extensively throughout cells.

The images on this page were used with the permission of the copyright owner, Molecular Probes..

Cytoskeleton Function

The image below shows both the actin fibers (in red) and microtubules (in yellow) in cow endothelial cells. The nuclei of the cells have been stained blue.

The cytoskeleton serves several key functions:

  • It supplies structure to cells and acts as a scaffolding for the attachment of many organelles.
  • It is responsible for the ability of cells to move.
  • It is required for the proper division of cells during cellular reproduction.

As we will see, changes in the cytoskeleton are observed in cancer cells. Cancer cells often show increased movement. In fact, metastatic spread of cancer is dependent on tumor cells that invade neighboring tissues.

The essential role of the cytoskeleton in the proliferation of cells has led to the use of drugs that inhibit the cytoskeleton as anti-cancer drugs. Examples of drugs that interfere with cytoskeletal function include Taxol® and vinblastine.

The image on this page was used with the permission of the copyright owner, Molecular Probes.


Cancer in cardiac cells - Biology

Ph.D, Mahidol University, Thailand
Post-doctoral, University of Wisconsin-Madison
Scientist, University of Wisconsin-Madison

My research has focused on understanding how redox state (the balance of reactive oxygen species (ROS) levels and antioxidant levels) regulates cancer progression and aggressive cancer phenotypes. We discovered that redox states inside the cells and in the tumor microenvironment, are significantly different in prostate cancer compared to normal prostate, both in cell culture models and in human tissues. Further, we applied cutting-edge technology called “nitroxides-enhanced MRI” to measure the redox state in prostate cancer tissue of living mice. Together, the expression levels of antioxidants (e.g. MnSOD or ECSOD) in prostate cancer biopsies combined with nitroxides-enhanced MRI technique, may serve as biomarkers to identify patients with localized cancers who are likely to progress to aggressive cancers.

We recently received R01 funding from National Cancer Institute (NCI) to investigate if simultaneously killing pre-existing mitochondria in cancer and preventing radiation-induced new mitochondria, would overcome radioresistance and improve radiation therapy. We screened FDA-approved drugs and identified several candidate compounds. We are in the process of identifying the underly mechanism(s) of these compounds that effectively inhibit the survival of post-irradiated cancer cells to improve radiation efficacy.

My laboratory’s research is also a part of a program project that is focusing on a novel approach that can reduce cancer treatments-induced cognitive impairment. We recently identified that redox-modified extracellular vesicles (RedoxEVs), lipid bilayer particles that are naturally released from cells, cause neuron cell death during cancer progression and cancer treatments. Couple with state-of-the-art resources at the University of Kentucky, we expect to provide new tools that can be used to elucidate mechanistic insights that will help to develop effective clinical approaches that designed to decrease cognitive impartment in cancer survivors. I am particularly excited about the potential opportunity and looking forward to the new discoveries that will stem from these projects.



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