Good news! Cancer is history (soon)!
"Primary cardiac tumors—cancers that develop in the heart—are exceptionally rare. New research in Science suggests that this low incidence may be because the heart beats: The continuous mechanical stress seems to stymie cancer growth.
In one experiment, researchers introduced potent cancer-driving mutations into mice that often develop tumors. Cancers occurred elsewhere in the body, but not in the heart. The team next created a side-by-side comparison within the same animal by observing a native heart still pumping under normal strain, and a donor heart kept alive with blood flow but without having to do the mechanical work of pumping. Tumors grew preferentially in the lower-strain heart.
Researchers saw the same effect after injecting several types of human cancer cells directly into heart tissue: In beating hearts, many remained as only small clusters, while in less-strained hearts, they grew larger.
Further analyses showed that cancer cells in beating hearts had weirdly shaped nuclei, condensed chromatin, more tightly packed DNA, and lower activity in genes tied to growth and cell division.
The team also rhythmically stretched cancer cells in the lab and concluded that strain alone could reproduce some of these antigrowth features. ... the team is already testing prototype devices designed to rhythmically compress superficial tumors, in the hopes of recreating the heart’s protective mechanism. ... it may be possible to recreate the effect of mechanical strain pharmacologically, providing new avenues for cancer treatments."
"... The rhythmic beating of the heart may play an unexpected role in protecting it from cancer. An international study ... demonstrates that the mechanical forces generated by cardiac contraction can significantly slow tumour growth in both mouse and human hearts. ..."
From the abstract (Perspective):
"Heart cancer is very rare in mammals. Moreover, the healthy adult heart does not regenerate. Human heart cells (cardiomyocytes) renew at an ~1% rate per year. The high mechanical load placed on cardiac tissue, which must overcome strong resistance to pump blood to all body organs, has been proposed to inhibit cardiomyocyte proliferation. Indeed, reducing the mechanical load on the heart promotes the expression of cell cycle markers in cardiomyocytes of patients whose hearts were unloaded by a ventricular assist device. ... report that the constant mechanical load to which cardiac tissue is subjected also inhibits the proliferation of cancer cells in the heart."
From the editor's summary and abstract:
"Editor’s summary
It is very rare for cancer to either form in or metastasize to the heart, suggesting that there is something that inhibits cancer growth in the cardiac microenvironment.
A key potential explanation is mechanical load. Ciucci et al. tested this idea by introducing cancer cells into rodent hearts and then in vitro engineering cardiac models with or without normal mechanical load.
They also compared human tissue samples from rare cardiac metastases and corresponding extracardiac tumors. The authors determined that increased mechanical load promoted Nesprin-2 signaling, which then led to changes in chromatin compaction and histone methylation, resulting in the suppression of cancer growth ...
Structured Abstract
INTRODUCTION
The heart is rarely affected by cancer; both primary cardiac tumors and metastases are uncommon despite the high vascularization of the myocardium. The mechanisms underlying this resistance remain unclear.
RATIONALE
Mechanical load has been proposed as a major mechanism halting cardiomyocyte proliferation early after birth, thus limiting the regenerative potential of the adult mammalian heart. We hypothesized that it could similarly hamper the proliferation of cancer cells in the heart.
RESULTS
We first used an in vivo genetic model of cancer in mice, in which Cre-mediated recombination results in the overexpression of mutated K-Ras and deletion of p53, to confirm that the heart resists oncogenic events. Despite a comparable extent of recombination in liver, heart, and skeletal muscle, multiple cancers arose at different anatomical sites but never in the heart.
In addition, we set up a mouse model of heterotopic heart transplantation to mechanically unload the heart in vivo. In this model, the aorta and pulmonary artery of the transplanted heart are surgically connected with the carotid artery and external jugular vein of the recipient animal, respectively, thereby restoring perfusion in the absence of mechanical load within the left ventricle. In parallel, we used engineered heart tissues in which mechanical load can be controlled at will.
In these models, mechanical load inhibited, whereas tissue unloading promoted the proliferation of lung adenocarcinoma, colon carcinoma, and melanoma cells within the myocardium.
To investigate the mechanisms underlying these effects, we used spatial transcriptomics to analyze samples of human cancers that gave rise to both cardiac and extracardiac metastases. We found that cardiac metastases shared a common transcriptional profile, independent from the origin of the primary tumor. Among the most up-regulated genes in cardiac metastases were histone demethylases. Consistently, cardiac metastases showed reduced histone 3 lysine 9 trimethylation and reduced chromatin compaction. Similar findings were observed in our experimental models of cardiac load modulation in which chromatin accessibility and histone methylation were altered at sites controlling cancer cell proliferation, as determined by single-nuclei assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing. Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation.
Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors.
CONCLUSION
Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation."
Heartbeat’s Mechanical Force Found to Suppress Tumour Growth (original news release)
The heart puts pressure on cancer growth (Perspective, no public access) "Mechanical forces in the heart prevent tumor expansion in mice"
Mechanical load inhibits cancer growth in mouse and human hearts (no public access)
