Why pancreatic cancer is so hard to beat

New Research Shows Why Pancreatic Cancer Is So Hard to Treat
Credit: Tuveson Lab, CSHL.

Researchers have moved an important step closer to understanding why pancreatic cancer is so hard to treat.

With a median survival of only 6 months and a 5-year survival rate of about 8%, patients tend to be diagnosed when the disease has already spread to other parts of the body – this is one part of the problem.

Another is that when treated with existing chemotherapy drugs, patients tend to benefit only slightly or not at all.

Why are pancreatic tumors so resistant to treatment? One reason is that the “wound”-like tissue that surrounds the tumors, called stroma, is much more dense than stromal tissue surrounding other, more treatable tumor types.

Stromal tissue is believed to contain factors that aid tumor survival and growth. Importantly, in pancreatic cancer, its density is thought to be a factor in preventing cancer-killing drugs from reaching the tumor.

Researchers suggest that a pancreas tumor is like a big raisin oatmeal cookie, with the raisins representing the cancer cells and oatmeal portion representing the dense stroma that makes up over 90% of the tumor.

Stromal tissue in the major form of pancreatic cancer is called pancreatic ductal adenocarcinoma, or PDA.

A recent study examines more about stromal tissue in PDA.

Stroma in PDA becomes what scientists call “desmoplastic.” Its dense, fibrous texture which presents a formidable barrier surrounding a tumor consists of structure-providing connective tissue; cells called fibroblasts which produce the main part of this connective tissue; and a plethora of immune cell types drawn to the tumor site as well as cells that form blood vessels, which bring nutrients to the tumor.

In the reported experiments, the researchers used organoid technology, in which organoids derived from tumors are for the first time “co-cultured” with one component of the stroma in which actual tumors grow.

The result is a more realistic rendering of what happens in the pancreas of cancer patients – and yet, in a stripped-down, simplified way, such that the effect of adding a single new factor, in this case from stroma, can be clearly parsed.

The additional factor added to the organoid culture was a cell-type called CAFs – cancer-associated fibroblasts, which happen to be the targets of past attempts to therapeutically target stroma in PDA.

Fibroblasts form part of the stroma and are typically non-cancerous, but contribute to the cancer’s development by secreting, among other factors, structure-providing molecules to the stroma.

But that is only one of their functions. The team in human- and mouse tumor-derived organoids, demonstrated something not previously known: fibroblasts come in at least two varieties in PDA, and possibly more.

“Our findings underscore that stroma is not unitary but rather heterogeneous in PDA,” says one author. “And this, in turn, provides our team and others in the field an opportunity to develop therapeutic agents that target specific fibroblast populations.”

The findings are published in Journal of Experimental Medicine.

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