Tumor release of lactate forces nearby cells into supportive role

Good news! Sounds a little bit bizarre! A tumor secretes milk.

"Tumors can force neighboring cells into supporting cancer growth by releasing lactate into their local environment ... how tumors, as they develop, recruit nearby cells called fibroblasts to work as their enablers. Fibroblasts are part of the “stroma,” or connective tissue of organs, and normally have important repair and maintenance functions. But cancer-associated fibroblasts (CAFs) acquire properties that allow them to assist tumors in ways that make the tumors more malignant and harder to kill.

The researchers also discovered that widely used cancer drugs, PARP-1 inhibitors, mimic one of the key steps in CAF recruitment, and thus may often hobble their own effectiveness by switching local fibroblasts to this cancer-enabling mode. ...

Scientists have known for decades that developing tumors often modify their local environments in ways that promote their own survival and growth. Cancer-associated fibroblasts are a central component of the tumor microenvironment in prostate, lung, colon and many other cancer types. Targeting these cells is therefore seen as a promising complementary approach to standard cancer treatment – and one that could work very broadly against cancers of different cellular and genetic origins. ...
But there was a second, surprising finding. A key step leading from tumor lactate secretion to fibroblast p62 suppression turned out to be the inhibition of PARP1, a DNA-repair enzyme. A class of cancer drugs called PARP1 inhibitors has the same effect, suggesting these drugs might be working partly against themselves by creating a more tumor-friendly microenvironment. ..."

From the abstract:

"Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity."

Tumor release of lactate forces nearby cells into supportive role | Cornell Chronicle

The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62 (open access)