Chapter 76
Cancer — 3
It’s unusual for someone to die from cancer unless it has undergone metastasis, spreading from one part of the body to another. Metastasis is what kills more than 90 percent of those who die from cancer, with many different proximal causes of death, particularly organ failures, not necessarily related to the body’s tumor burden. Metastasis-initiating cells acquire aggressive features that enable invasive migration via blood vessels or lymphatics in various ways, including evasion of the immune system, epigenetics, and metabolic adaptation. Sampling blood for circulating tumor cells or cell-free tumor DNA can track this migration, which we’ve learned can be quite aggressive while we sleep. In a study with samples from individuals with breast cancer taken at four o’clock and ten o’clock in the morning, 78 percent of circulating tumor cells were found during sleep. While there’s certainly no practical strategy for avoiding sleep to reduce metastasis, this study points to how aggressive cancer may be in exploiting our immune system.
It is remarkable just how opportunistic cancer cells can be. For cancer cells circulating in the blood, just two per ten thousand can establish metastasis. Unfortunately, healthy cells in some organs express proteins on their surface that promote the seeding of cancer cells. Only in recent years have we learned how cancer can hijack neurons and neural circuits, while the poor nervous system is trying to police cancer’s initiation and progression. Back in 2019, direct synapses were noted between a type of brain tumor and neurons, summarized in four words: “Gliomas are electrically active.” In many ways, this finding, also seen in a companion paper on metastatic brain cancer, gave a solid foundation to the relatively new field of cancer neuroscience. Subsequently, a variety of neurotransmitters and nerve growth factors appeared to be involved in forming membrane tube connections, not just in the brain but also in the spinal cord and peripheral nervous system. Certain driver gene mutations, like p53, can even reprogram nerve cells to make them secrete epinephrine and norepinephrine that can, in turn, stimulate tumor growth. The neuron–cancer cell connections can suppress the immune response. Reprogramming sympathetic nerves has been shown to promote T cell exhaustion and interfere with immune therapy for cancer. These new insights on the role of cancer cell–neuron connections have led to clinical trials across an array of cancer types, ranging from brain to breast, pancreas to prostate, with various repurposed drugs like propranolol, clonidine, or botulinum toxin.
The review of neuroscience and cancer by Rebecca Mancusi and Michelle Monje summarized the opportunity nicely: “Although targeting nervous system–cancer interactions may not by itself be sufficient to eradicate a tumor, this may be a necessary component of effective therapeutic regimens for currently intractable cancers such as high-grade gliomas and pancreatic cancers.”
The cancer cell hijacking isn’t limited to neurons. For decades, the ability of cancer to hijack blood vessels to create its own blood supply led researchers to develop drugs that block new blood vessel formation, known as antiangiogenesis agents, such as antibodies (bevacizumab, Avastin) and vascular endothelial growth factor, which have been approved and used for certain types of cancer, but with limited success. While we’ve long known of cancer’s ability to evade our immune response, observing single cells revealed yet another dimension of cancer’s hijacking behavior: it stole the mitochondria, powerhouse of the cell, from T cells! This is a double whammy, empowering the cancer cells while simultaneously dismantling the immune response, predominantly orchestrated via T cells. Like in the movie Catch Me If You Can, cancer cells can even switch their driver genes and cell identity during therapy. This has been seen in both lung and prostate adenocarcinoma.