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How does cancer do that? Pancreatic cancer cells find ways to survive

September 18, 2019 | by CTCA

Pancreatic cancer
But, despite these incredible advancements, one of the most common cancers continues to vex doctors and researchers: pancreatic cancer.

We are living in an incredible age of cancer care. Advanced genomic testing gives doctors a deep dive inside cancer cells and the gene mutations or biological features that may be driving a tumor’s growth. Targeted therapy drugs have been developed to attack those mutations and are designed to spare healthy cells. Immunotherapy drugs, designed to strip away cancer cells’ ability to hide from the immune system, are standard-of-care treatment for many difficult cancers, including lung cancer and melanoma.

But, despite these incredible advancements, one of the most common cancers continues to vex doctors and researchers: pancreatic cancer. “It’s a very hard cancer to have,” says Arturo Loaiza-Bonilla, Vice Chairman of the Department of Medical Oncology at Cancer Treatment Centers of America® (CTCA). “It’s a very hard cancer to treat.” Pancreatic cancer cells are particularly evasive and resilient. They have cell mutations for which no current treatments are available. They form tumors that entangle themselves into surrounding blood vessels and tissue, making surgical removal difficult. And they create a protective cocoon around the tumor that keeps it shielded from treatment. “Pancreatic cancer cells are able to survive a lot of things—radiation therapy, chemotherapy, having no oxygen or blood supply,” Dr. Bonilla says. “They just survive for a long time.”

In recent years, science has cracked open the door on some of pancreatic cancer’s mysteries and offers hope that the era of precision medicine may make an impact on the detection and treatment of pancreatic cancer. Hundreds of clinical trials are underway in search of innovative treatment options for pancreatic cancer. And promising research has enlisted tiny cellular bubbles called exosomes that may be key to diagnosing pancreatic cancer early and treating it.

A difficult diagnosis

Pancreatic cancer is the 11th most common cancer in the United States, with more than 56,000 cases diagnosed each year, according to the National Cancer Institute (NCI). The five-year survival rate for a patient diagnosed with pancreatic cancer is less than 10 percent. The average age of a patient diagnosed with pancreatic cancer is 70; the average of a patient who dies from the disease is 72. The statistics of new cases and deaths from cancer of the pancreas have remained virtually flat over the last 25 years, even as new treatments for other cancers have produced positive outcomes The lack of movement frustrates researchers and doctors alike—they know many of the reasons why pancreatic cancer is difficult to treat, but they have not yet found breakthroughs to attack them. “It’s multifaceted,” Dr. Bonilla says. “There’s not one reason why this cancer is difficult to treat, but several.” They include:

Late diagnosis: Pancreatic cancer is detected in stage IV of the disease more than half the time. The disease produces few, if any, symptoms in early stages. “Pancreatic cancer is a silent cancer,” Dr. Bonilla says. “By the time it is diagnosed, most often, the cancer has already spread to the liver or other parts of the body.”

Early warning signs of pancreatic cancer include:

  • Dark urine
  • Weight loss
  • Digestive issues
  • Nausea

Other symptoms include:

  • Abdominal or back pain
  • Extreme fatigue
  • Swelling and bloating
  • Jaundice

Since the pancreas produces insulin that helps regulate blood sugar, a diagnosis of diabetes may also be an early symptom of cancer.

Inoperable tumors: Pancreatic tumors are particularly invasive in the abdomen and often cannot be completely removed during surgery. “When pancreatic cancer is detected, it’s mostly advanced, taking over the blood vessels in the back of the belly,” Dr. Bonilla says. “So, it can’t be removed because those blood vessels are so intertwined in the tumor.”

Shield of armor: Pancreatic cancer cells create a cocoon of collagen fibers around the tumor that shield it from outside forces. These fibers, which are like scar tissue, form when cancer cells produce enzymes that damage healthy tissue, leading to the formation of collagen that eventually envelopes the tumor. This process is called desmoplastic reaction, or desmoplasia, and is a feature of several cancers. “The collagen grows around the tumor, which still grows and does damage,” Dr. Bonilla says. “Meanwhile, the immune system or chemotherapy doesn’t make it through the barrier because it’s too hard to penetrate.”

Biomarkers with no targets: In cancer, biomarkers are genetic features or mutations in cells that may drive a tumor’s growth. The identification of some biomarkers has led to the discovery of targeted therapy and immunotherapy drugs designed to attack those biomarkers. Pancreatic tumors often are driven by mutations in the KRAS and TP53 genes, two of the most common markers found in tumors. No targeted therapy drugs have been developed to target those gene mutations.

No immune response: While some tumors contain dormant immune cells called lymphocytes that may be awakened by immunotherapy drugs, pancreatic cancer cells are low in immunogenicity, that is they are less likely to generate an immune response,” Dr. Bonilla says. “So, there are not a lot of lymphocytes in the tissue.” With few immune cells in the tumor and a barrier keeping immune cells from entering the tumor, immunotherapy drugs usually are not a treatment option for pancreatic cancer.

Hope for the future in a tiny package

As persistent as pancreatic cancer cells are to resisting treatment, so are doctors and researchers in searching for new treatments. Among the most promising avenues of research involve one of the smallest of entities in the human body: exosomes. These tiniest of vesicles are like carrier pigeons delivering messages from one cell to another. These messages often include instructions that give cells new duties to perform. In cancers, researchers have found evidence that tumors use exosomes to:

  • Turn healthy cells into cancer cells
  • Release proteins that help cancer cells grow and/or resist treatment
  • Suppress the immune system, allowing cancer cells to grow more aggressively
  • Send instructions to cancer cells to metastasize (or travel to distant locations in the body)

Because exosomes from cancer cells contain instructional information, researchers surmise that data may be tapped and decoded to help in the early detection and treatment of several cancers, especially pancreatic cancer. “Circulating exosomes have demonstrated potential as reliable candidates for the early diagnosis of pancreatic cancer, for use in screening high-risk individuals without clinical presentation of cancer, and for monitoring the course of the disease,” researchers in China write. “Accumulating evidence has revealed that exosomes can indicate the clinical management of pancreatic cancer, improve overall survival and prevent organ-specific metastasis.”

What are exosomes?

Exosomes are:

  • Tiny bubbles of cellular material that live outside cells
  • Believed to carry messages and other materials, referred to as “cargo” from one cell to another
  • 30 to 100 nanometers in diameter (a nanometer is one-billionth of a meter)
  • Believed to promote diseases, such as cancer, Alzheimer’s and Parkinson’s

Researchers at MD Anderson Cancer Center are considering ways exosomes may be able to reduce KRAS levels in pancreatic tumors. Nearly all pancreatic cancers are pancreatic ductal adenocarcinomas (PDA), and nearly all PDAs have mutations in the KRAS gene. In laboratory mice, KRAS levels in pancreatic tumor cells were reduced and gene activity was suppressed using engineered exosomes, researchers said. Their study also showed that treatment using exosomes weakened the tumor’s desmoplastic cocoon, slowed the growth of pancreatic cancer cells and prompted cancer cells to kill themselves, a process called apoptosis.

Researchers in London also are exploring exosomes’ potential as a drug delivery tool. In theory, exosomes could be isolated in a lab and reprogrammed with a drug or new instructions. And since exosomes can travel freely throughout the body, they may be able to deliver their new cancer-fighting properties to pancreatic cancer cells that drugs or immune cells may not reach. “Currently, exosomes are being studied for early detection of pancreatic cancer, and they have also been linked to resistance to current treatment options and the increased risk of recurrence in pancreatic cancer,” Dr. Bonilla says. “More data is needed to validate this research, but it is quite intriguing.”

More about pancreatic cancer

  • The pancreas is located behind the stomach and helps the body generate digestive fluids and insulin that regulates blood sugar.
  • Risk factors for pancreatic cancer include smoking, obesity, diabetes and a family history of the disease.
  • Men are at a higher risk of developing pancreatic cancer than women. African American men have the highest risk.
  • About 95 percent of pancreatic cancers are exocrine tumors, forming in the enzyme-producing exocrine cells. The remaining 5 percent of tumors in the pancreas form in endocrine cells.

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