Pancreatic cancer desmoplastic reaction and metastasis (EC, 2015)

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Encyclopedia of cancer, 2015

Definition

Desmoplastic reaction in pancreatic cancers is characterized by a marked increase in proliferation of stromal cells, accompanied by a synthesis and deposition of tumor-promoting extracellular matrix (ECM) proteins such as collagen, laminin, fibronectin, and vitronectin. Distinct cell types including endothelial cells, immune cells, fibroblasts, endocrine cells and, in particular, pancreatic cancer stellate cells (PSCs) that are embedded in the extracellular matrix constitute the desmoplasia – fibrotic sarcoma – of the pancreatic cancer. In pancreatic cancer, desmoplastic stroma can contribute to 90 % of the tumor volume. Recent  studies  have shown  that the desmoplastic reaction plays a greater role in metastatic tumor progression and drug resistance observed in pancreatic cancer.

Characteristics

Histopathological studies have defined that the desmoplastic reaction is mediated by the copious secretion of different ECM proteins by both the stromal and cancer cells. These ECM proteins include stromal cell-derived biglycan, collagen I/III/IV, decorin, FAP-α, fibronectin, hyaluronic acid, laminin, lumican, MMP-2/9/11, osteopontin, periostin, SPARC/osteonectin, tenascin C, thrombospondin 1/2, as well as cancer cell derived ECM proteins, such as TIMP1/2, tPA, uPA, versican, and vitronectin. Of the different types of stromal cells, pancreatic stellate cells play a major role in this process. In the normal pancreas, PSCs are located in the periacinar space and account for approximately 4 % of all pancreatic cells. These stellate cells in response to tumor cell derived growth factors, such as transforming growth factor-β (TGFβ), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), Wnt-ligands, Hedgehog ligands, and/or oxidative stress, transdifferentiate into α-smooth muscle actin (α-SMA)-expressing “activated PSC.” ECM component of the desmoplastic reaction is primarily secreted by these activated PSCs. Therefore, the ratio of activated PSCs in relation to nondifferentiated stellate cells has been defined as Activated Stroma Index (ASI), and it has been used to define the extent of desmoplastic reaction in pancreatic cancer. In fact, higher ASI has been shown to predict poor prognosis in pancreatic cancer patients. This clinical correlation also underscores the tumorpromoting role of the associated desmoplastic stroma in pancreatic cancer.

Table 1. ECM proteins of desmoplastic stroma in tumor cell metastasis

ECM protein Role in metastasis
Collagen I, III, IV Invasion, metastasis, angiogenesis
Fibronectin Migration
Lumican Migration, invasion
MMP 2/9/11 Invasion
Osteopontin C Invasion
Osteonectin/SPARC Invasion
Tenascin Invasion
Thromospondin 1/2 Invasion, angiogenesis
TIMP 1/2 Invasion

Desmoplastic stroma and pancreatic cancer progression

In addition to ECM proteins, activated PSCs of the desmoplastic stroma secrete proliferative cytokines. Excess deposition of the desmoplastic constituents leads to a hypovascular and fibrotic pancreatic tumor microenvironment, which promotes epithelial to mesenchymal transition (EMT) of pancreatic cancer cells along with an increased drug resistance. The role of PSCs in such pancreatic cancer progression is evidenced by the studies in which the coculture of pancreatic cancer cells and PSCs leads to the expression of EMT markers and the stemness genes such as nestin, ABCG2, and LIN28 in the pancreatic cancer cells. The desmoplastic stroma also contributes to mechanisms by which invading tumor cells evade host immune surveillance. Galectin1 and fibroblast activation protein-a synthesized by the activated PSCs bind to membrane glycoproteins of T-cells, thereby inducing apoptosis of tumor-targeting T-cells.

Desmoplastic stroma and metastasis of pancreatic cancer

The desmoplastic reaction evoked by the PSCs form the major determinant of pancreatic cancer malignancy and metastasis. Interaction of PSCs with the pancreatic cancer cells leads to the production of migratory and invasive ECM proteins (Table 1).

There seems to be bidirectional signaling between the tumor cell and the activated PSCs of the desmoplastic stroma. For example, extracellular matrix metalloproteinase inducer (EMMPRI) secreted by the pancreatic cancer cells induces the production of MMP-2 by PSCs, which facilitates the invasive migration of the cancer cells. Similarly, the invasive property of tumor cells via SERPINE2 is promoted only in the presence of ECM produced by the PSCs. In addition, PSCs have been shown to promote EMT in pancreatic cancer cells that contribute significantly towards the dissemination and metastasis of cancer cells. PSCs have also been observed to migrate to the metastatic site where they appear to enhance metastasis through their physical interaction with pancreatic cancer cells. Owing to the abundance of ECM in desmoplastic stroma, integrins such as ITGA6, ITGB4, and ITGB5; and ephrins  such  as EPHA2 further contribute to the metastatic process in pancreatic cancer. Intriguingly, a distinctive subpopulation of PSCs expressing the surface marker CD10 is observed to promote tumor invasion and growth better than the CD10-negative subpopulations.

Management of pancreatic cancer metastasis by targeting the desmoplastic reaction components using standard chemotherapeutic agents, such as gemcitabine and erlotinib, offer limited scope  in  pancreatic  cancer  management.  It appears that the extensive ECM associated with the desmoplastic stroma of pancreatic cancer acts as a physical barrier that prevents the uptake of chemotherapeutic  agents  by  the  tumor  cells. Therefore,  there  is  an  emerging  interest  in targeting the tumor microenvironment, particularly  the  desmoplastic/stromal  components  of pancreatic  cancer.  Several  antifibrotic  agents have  shown  promise  in  preclinical  trials  and include polyphenols, vitamin E, inhibitors of the rennin–angiotensin system, inhibitors of hedgehog signaling, enzymatic modes of elimination of hyaluran, and the depletion of tumor–associated fibroblasts. It has been shown that ellagic acid, a plant–derived phenol, has been shown to inhibit the activation of PSCs. Different isomers of vitamin E have been shown to reduce desmoplastic reaction in animal models of pancreatic cancer. While a–tocopherol has been shown to reduce desmoplastic  response,  tocotrienols  have  been reported to exhibit a cytotoxic effect on PSCs by mediating autophagy and apoptosis. In addition, inhibitors of the renin–angiotensin system have been shown to inhibit the development of pancreatic fibrosis. Signaling pathways, which can  revert  the  activated  PSCs  to  quiescence, have  been  interrogated  in  the  past  decade. Retinoic acid-mediated inhibition of ERK, JNK, and p38MAPK has been demonstrated to induce such  quiescence  in  PSCs.  Overexpression  or reintroduction of PPAR–g, C/EBP–a, and albumin has also been suggested to inactivate PSCs. Tumor-associated      fibroblasts      of      the desmoplastic stroma produce several ECM proteins   including   fibroblast   activation   protein (FAP), a type II integral membrane glycoprotein that   is   associated   in   the   turnover   of   the ECM.  Therefore,  subcutaneous  administration of FAP-specific antibodies has been reported to attenuate  tumor  growth  in  mice  models  of pancreatic   cancer.   Within   the   desmoplastic stroma,  mast  cell-derived  interleukin-13  and tryptase promote the proliferation of pancreatic stellate cells. Therefore, masitinib, a mast cell/ stem cell growth factor inhibitor, in combination with gemcitabine was assessed for its efficacy in a phase III pancreatic cancer patient trial. The results indicated that masitinib conferred survival advantage to at least a subgroup of pancreatic cancer patients, thus validating mast cells as a therapeutic target to a certain extent.

In addition, inhibition of candidate signaling pathways involved in the activation of PSCs has been tested for their ability to attenuate pancreatic cancer progression. Hedgehog signaling plays a crucial role in the epithelial to mesenchymal transition of the pancreatic cancer cells. Hedgehog ligands are secreted from the tumor epithelium and the activation of hedgehog signaling takes place in the adjacent stromal compartment. Administration of IPI-926, a hedgehog pathway inhibitor, was reported to improve the uptake of gemcitabine by the pancreatic tumor cells in the mouse models of pancreatic cancer. In such animal model, it has also been shown that the enzymatic depletion of hyaluronan/ hyaluronic acid using recombinant hyaluronidase (PEGPH20) can increase vascular permeability and drug delivery.

Similarly, depletion of stroma by CD40activated macrophages has also been documented to improve survival in patients with PDAC. In a small cohort study with CD40-activated macrophages in patients with advanced pancreatic cancer, CD40-activated macrophages induced tumor attenuation, facilitated the depletion of desmoplastic stroma, and increased patient survival. Another strategy involves the differential expression of SPARC, an albumin transporter in cancer-associated fibroblasts. Since tumor cells do not express SPARC, nab-paclitaxel, an albumin bound form of paclitaxel, can be targeted to cancer-associated fibroblasts. Coadministration of the maximum tolerated dose of gemcitabine with nab-paclitaxel (MPACT trial) in patients with advanced pancreatic cancer resulted in an objective response rate of 48 %, thus validating nab-paclitaxel as a stromal targeting agent. All of these results point to the desmoplastic stroma as a potential therapeutic target for the clinical management of pancreatic cancer.

Conclusion

Better prognosis and therapeutic management of pancreatic cancer requires identification of stromal targets and inhibition of stromal–pancreatic cancer cell communication. Understanding the intercellular communication among the different cellular populations within the tumor microenvironment and characterization of the critical factors involved in such communication could lead to better clinical management of pancreatic cancer.

References

Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar  RK,  Ramm  GA,  Buchler  M,  Friess  H,

McCarroll JA, Keogh G, Merrett N, Pirola R, Wilson JS (2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic cancer cells. Pancreas 29:179–187

Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9:454–467

Grzesiak J, Ho JC, Moosa AR, Bouvet M (2007) The integrin–extracellular matrix axis in pancreatic cancer. Pancreas 35:293–301

Lunardi S, Muschel RJ, Brunner TB (2014) The stromal compartments in pancreatic cancer: are there any therapeutic agents? Cancer Lett 28:147–155

Schober M, Jesenofsky R, Faissner R, Weidenauer C, Hagmann W, Michl P, Heuchel RL, Haas SL, LoЁhr JM (2014) Desmoplasia and chemoresistance in pancreatic cancer. Cancers (Basel) 21:2137–2154

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