Tumor spread along nerves, adenocarcinoma , and Macrophages

Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC).

Neural invasion is associated with poor outcome, yet its mechanism remains unclear.

Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.



Perineurial invasion (PNI) by cancer is associated with poor prognosis in patients with carcinomas of the gastrointestinal tract, head and neck, pancreas and prostate.1 Most patients with pancreatic ductal adenocarcinoma (PDAC) undergo palliative treatment rather than curative surgery, due to distant metastases or neural spread along extra pancreatic nerves. Most importantly, these patients tend to suffer from debilitating neuropathic pain and poor quality of life.2

The prevalence of PNI varies considerably among cancer types, and reaches 80–100% in pancreatic cancer.3, 4 Recent studies have suggested that the tumor microenvironment has a role in cancer dissemination along nerves.5, 6 A prominent inflammatory infiltration is present around preinvasive pancreatic lesions and persists through invasive cancer.7 Of relevance, there is evidence that the neural microenvironment of invaded nerves has a unique inflammatory profile.8, 9

Recently, we and others described the presence of immunocytes in the perineurial niche.8, 9, 10 Clinical and experimental studies have demonstrated a strong association between macrophage density and cancer cell metastasis in PDAC. Furthermore, targeting tumor-associated macrophages by inhibiting either the colony-stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) improves chemotherapeutic efficacy and inhibits metastasis.11, 12, 13, 14 In the normal nerve, macrophages that can be derived from either resident immune cells or from circulating monocytes participate in regeneration of peripheral nerves.9, 15 However, in the nerve-cancer microenvironment, the origin and polarization of these macrophages, as well as their role in PNI, is not well defined.

It has been suggested that glial-derived neurotrophic factor (GDNF) can also promote PNI.16, 17, 18 GDNF expression in human samples was also associated with PNI and reduced survival.19 Immunofluorescent imaging revealed expression of the GDNF receptor, GDNF family receptor α-1 (GFRα1) and its co-receptor RET by pancreatic cancer cells.9 Although previous clinical and experimental data implicated the involvement of RET in PNI, no direct evidence links RET activity with PNI in transgenic animal models or in patients with PDAC. To detect tissue-specific factors influencing neural invasion by cancer cells, we characterized the perineurial environment in human samples and in a series of transgenic mice models expressing mutations in the Kras, p53, GDNF and CCR2 genes.

The current study provides direct evidence that upregulation and activation of RET by perineurial macrophages induce perineurial spread of PDAC.



Macrophages are a prominent component of the perineurial microenvironment

The patterns of inflammatory response secondary to pancreatic tumorigenesis are distinct from those of chronic pancreatitis.8, 11 Furthermore, an immune cell profile is stage-dependent in many types of cancer.20, 21, 22 To investigate the involvement of immunocytes in the perineurial microenvironment during tumorigenesis, we evaluated pancreata excised from 2-, 3- and 6-month-old KPC mice with normal pancreas, PanIN and PDAC, respectively. Immunofluorescent analysis revealed significantly greater infiltration of lymphocytes around nerves in PDAC and PanINs than around nerves in normal pancreas (P<0.01, n=10 per group, Figures 1a and b). Macrophage infiltration was more prominent around nerves invaded by cancer than around nerves in PanIN lesions or normal pancreas (P<0.001, Figures 1a and b). Hence, recruitment of immunocytes to the neural niche occurs during pancreatic carcinogenesis.


Examining the early lives of two men who died of lung cancer

About 55% of our lifespan is affected by environment and our behavior. Two men I know died of lung cancer, one is my father and another my client – providing non medical in home care.

My father

At age 21, he started to smoke and by the time he reached the age of 40, he has tuberculosis (bacterial). He worked day and night as driver, mechanic. And worked in copper and nickel mines as security guard and mechanic. He also worked in places with asbestos and other metal dusts/toxins. 15 years before he died, he already stopped smoking. 5 to 10 years before he died, he experienced back pain.  During the last 5 years of his life, he has chronic cough at night. And at the time of his diagnosis, a blood vessel erupted in one of his eyes. Lung cancer was identified via an MRI and CAT scan. He lived his last 9 months with no meds, only 2 oxygen tanks, juice of green papaya and apples, massage and prayers. He died at 64 yrs of age at home in the Philippines, a year before that he spent 9 months in the USA.

My client

He died at 77 yrs of age, a tall and successful American who had lived in New York, Colorado and California. He started taking Acyclovir for shingles (viral) at young age and TUMS for indigestion. At one time, he was exposed to gold dust.  He loved sweet desserts. He loved challenges and worked hard and brushes off any pains he can feel. He loved art and his family, helping them succeed.

He was diagnosed with adenocarcinoma, a hormonal cancer that spreads in many organs. During the last week of his life, MRI scans revealed growing nodes of small strokes (a dozen) and a rapidly progressing lung cancer. He had surgery for small intestine cancer and other surgeries including 2 lung cancer and stroke.

Connie’s notes: Avoid metal toxins. Virus and Bacteria invades our cells and our immune system must always be strong which can be weakened by stress, lack of sleep, unhealthy living, absence of whole foods and other unknowns.




Recognizing the most common warning signs of a stroke

Three telltale symptoms occur in 75% of all strokes, often in combination. Don’t ignore them — even if they’re short-lived.

Published: June, 2017

Image: © American Heart/Thinkstock

Every 40 seconds, someone in the United States has a stroke. Also known as “brain attacks,” strokes result from an injury to a blood vessel that limits blood flow to part of the brain. Rapid diagnosis and treatment can prevent potentially devastating disability or death — which is why everyone should know the common warning signs of a stroke.

In 2013, the American Stroke Association unveiled a stroke awareness campaign based on the mnemonic FAST. Around that the time, a national survey suggested that 28% of Americans didn’t know any stroke symptoms, and nearly half weren’t sure what to do if they experienced or witnessed the symptoms of a stroke. But four years later, things seem to be improving.

“The FAST campaign has had a positive impact by helping the public become more aware of stroke symptoms,” says stroke specialist Dr. Christopher Anderson, assistant professor of neurology at Harvard Medical School. As far as memory aids go, FAST makes sense because the first three letters (which stand for Face, Arm, and Speech) cover the most stereotypical symptoms and together account for about 75% of the symptoms stroke patients experience. They’re caused by strokes that occur in the large hemispheres in the front part of the brain, explains Dr. Anderson. Often, but not always, people have more than one symptom.

FAST enough?

Sometimes, people who are having a stroke experience leg weakness (which can cause balance or walking problems) or have trouble seeing (such as blurred or double vision). These less-common symptoms usually occur from strokes that occur in a smaller area in the back part of the brain. Some neurologists argue that adding two additional letters before FAST — B for balance and E for eyes — to make the mnemonic “BE-FAST” would help people recognize even more strokes.

But Dr. Anderson isn’t sure that’s a good idea, for a couple of reasons. First, in a moment of panic, it’s not easy to quickly remember what four letters stand for, let alone two extra ones. Second, balance is a tricky sign because a lot of older people have balance problems now and then. Many other things, such as low blood pressure or inner ear problems, can cause dizziness or balance issues. When caused by a stroke, balance problems are often accompanied by other symptoms. “If you’re having a stroke, your balance may be off, but one leg also feels heavy, or you can’t see quite right,” Dr. Anderson says. When those symptoms appear together, that’s concerning and should be evaluated right away, he adds.

The eye symptoms can be elusive; they include blurred vision, seeing double, and trouble focusing. Sometimes a stroke cuts off part of the visual field. As a result, people can’t judge the space around them, and they’ll do things like bang their shoulder while walking through a doorway.

Short-lived symptoms: Still alarming

It’s very important not to brush off short-lived stroke symptoms. They may represent a transient ischemic attack, or TIA — a temporary decrease in blood flow to the brain, sometimes called a ministroke.

“For instance, a woman might notice that while her husband was reading before bed, his arm got a little clumsy and he couldn’t see right. But then it went away.” Just because a symptom goes away doesn’t mean it’s not still scary, warns Dr. Anderson. A TIA is an important sign that something is wrong and could lead to a more serious stroke if not addressed.

Another classic scenario is a person who says, “That’s funny, I can’t feel one side of my mouth,” and then their speech becomes garbled. Or a person might say, “I was cooking and I dropped the knife. I picked it right up, but then I dropped it again.” In all of these instances, you should call 911 right away.

If you’re calling for someone else, be sure to note the time you first noticed the symptoms, or when the person was “last seen well” without symptoms. The information can be vital for doctors, because the most common stroke treatment should be given within a certain time frame.

Lung Cancer deaths from 55-70

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Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women (not counting skin cancer). In men, prostate cancer is more common, while in women breast cancer is more common. About 14% of all new cancers are lung cancers.

The American Cancer Society’s estimates for lung cancer in the United States for 2016 are:

  • About 224,390 new cases of lung cancer (117,920 in men and 106,470 in women)
  • About158,080 deaths from lung cancer (85,920 in men and 72,160 in women)

Lung cancer is by far the leading cause of cancer death among both men and women; about 1 out of 4 cancer deaths are from lung cancer. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.

Lung cancer mainly occurs in older people. About 2 out of 3 people diagnosed with lung cancer are 65 or older, while less than 2% are younger than 45. The average age at the time of diagnosis is about 70.

Lifetime chance of getting lung cancer

Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in 14; for a woman, the risk is about 1 in 17. These numbers include both smokers and non-smokers. For smokers the risk is much higher, while for non-smokers the risk is lower.

Black men are about 20% more likely to develop lung cancer than white men. The rate is about 10% lower in black women than in white women. Both black and white women have lower rates than men, but the gap is closing. The lung cancer rate has been dropping among men over the past few decades, but only for about the last decade in women.

Statistics on survival in people with lung cancer vary depending on the stage (extent) of the cancer when it is diagnosed. For survival statistics based on the stage of the cancer, see “Non-small cell lung cancer survival rates by stage.”

Despite the very serious prognosis (outlook) of lung cancer, some people with earlier stage cancers are cured. More than 430,000 people alive today have been diagnosed with lung cancer at some point.

Other cancers in increasing trend in the West:

The incidence of adenocarcinoma of the esophagus has been increasing rapidly in Western countries, such as the United States, Australia, France, and England, in recent decades, most likely as a result of increases in overweight/obesity, chronic gastric reflux, and the premalignant condition Barrett’s esophagus.57 These increases may also be related to the declining prevalence of H. pylori infection, as H. pylori appears to be associated with a reduced risk of esophageal adenocarcinoma.

Survival: Most people with esophageal cancer eventually die of the disease because it is usually diagnosed at a late stage. In the United States, 18% of white patients and 12% of black patients survive (relative survival) at least five years after diagnosis.33 In Europe, the average five-year relative survival rate is 12%.

Connie’s notes: How can we detect cancer early?

My brother’s friend has adenocarcinoma and was detected late already when the pain in the hip and other areas in the body was dismissed and was not pursued to have a deeper origin. There was a skin disorder on the chest last month and now he has 3months to live with his tongue slowly deteriorating in movement and the hip pain unbearable. He is 64 yrs of age, over weight and on meat diet. His wife works as a nurse at Kaiser.  He is a scientist. His father died of Parkinson, 10 yrs ago, at 70 yrs of age. He lives in Northern California.