Several stroma-targeting drugs are currently being tested as new treatment strategies to reduce chemoresistance in PDAC. One of the more appealing targets of the tumor stroma is the potent cytokine TGFβ which regulates developments, differentiation, and homeostasis in mammalian [75]. TGFβ binds to TGFβ receptor 1 or 2 to inhibits cell proliferation, motility, invasion, EMT, and metastasis [76] and its tumor-inhibitory effect is controlled by Smad-dependent TGFβ signaling [77]. Indeed, in human prostate cancer, overexpression of TGFβ1 correlates with collagen I levels, suggesting that TGFβ can be directly linked to the desmoplastic process [35]. Furthermore, knocking down Smad 3 abolishes collagen fibrosis induced by the EMT-regulator Snail, hence corroborating the role of TGFβ as a crucial signaling pathway in the propagation of the desmoplastic reaction [78]. Moreover, Smad4 is frequently mutated in PDAC and this could be one of the reasons for the resistance to the growth inhibitory effects of TGFβ [35]. In this line, some TGFβ receptor 1 inhibitors, such as SB431542 and SB525334, have been developed and tested in combination with gemcitabine, resulting in a higher cytotoxic effect compared to gemcitabine alone due to an increased delivery and penetration of the drugs into the tumor (desmoplastic) tissues [79].

Moreover, the hyaluronan cell surface receptor CD44 has a critical role in pancreatic carcinogenesis [80] such that disruption of the hyaluronan-CD44 complex is a crucial therapeutic target to prevent PDAC drug resistance [80]. Indeed, the compound, 4-methylumbelliferone (4-MU), by inhibiting hyaluronan synthesis and accumulation on cancer cells and their surrounding stroma, blocked cell proliferation, migration, and spreading in several tumor cell types [81,82] and reduced bone metastases in breast cancer (Figure 2) [83]. In both PDAC cell lines and in vivo, 4-MU slowed the development and progression of the disease and also increased tumor response to gemcitabine [84,85,86]. In a similar way, PEGylated human recombinant PH20 hyaluronidase (PEGPH20) acted as a hyaluronan “consumer” enhancing the delivery of chemotherapeutic agents such as doxorubicin and gemcitabine [55,74]. Injection of PEGPH20 into KPC mice tumors rapidly degraded hyaluronan, restored the patency of intra-tumoral vessels, increased vessel diameter and highly reduced the high interstitial fluid pressure within the tumors to normal levels [12]. Importantly, these alterations increased the macromolecules permeability and the combined treatment of gemcitabine with PEGPH20 remarkably improved treatment efficacy by reducing metastases and doubling the median survival time in mice [87].

Further, the enzymatic degradation of ECM components has also been proposed as a possible complementary therapeutic approach against PDAC. Several studies using hyaluronidase showed improved cancer sensitivity to chemotherapeutics and enhanced permeability to drugs in cultured multicellular spheroids [88]. Similarly, collagenases have also displayed beneficial characteristics by increasing the penetration of macromolecules. However, their sensitivity to and stability at physiological pH might be a therapeutic hindrance that has not yet allowed this enzyme to be clinically available [89]. We have proposed a double edged targeting of the hyaluronan-CD44 pathway by combining 4-MU as hyaluronan production inhibitor and bromelain as CD44 inhibitor [90], since this combination has not been experimentally tested yet. Lastly, Hedgehog (Hh) is a signaling pathway that is abnormally activated in most pancreatic cancers leading to cancer initiation, progression and metastatic development [91,92]. More recently, it has been related to the beginning and maintenance of the desmoplastic reaction. Indeed, Hh stimulates the differentiation of myofibroblasts and induces stroma-derived growth promoting molecules [93,94]. There is also some evidence that supports the existence of an interplay between Hh signaling and TGFβ, both being tightly connected with the desmoplastic reaction and involved in fibrosis [94]. Further, it was demonstrated that blocking Hh signaling, both in vitro and in vivo, with the small molecule compound, cyclopamine, markedly improved drug delivery and abrogated pancreatic metastasis [95,96]. Multiple studies have been conducted to verify whether the combined treatment of Hh signaling inhibitors with chemotherapeutic agents can have synergistic anticancer effects [97]. Indeed, the inhibition of the Hh signal with the semisynthetic analogue of cyclopamine, IP-926, reduced the desmoplastic reaction and improved tumor vascularity [98]. A phase Ib trial demonstrated that IPI-926 reduced tumor desmoplasia and increased gemcitabine delivery, such that 31% of patients displayed a partial response and 63% of them showed a reduced expression of the marker Carbohydrate Antigen 19-9 (CA 19-9) in their tumor tissues [99].

In summary, the desmoplastic reaction creates a unique microenvironment, which stimulates tumor growth/progression and forms a “physical barrier” to chemotherapy permeability. Hence, several strategies have arisen to improve chemotherapeutic efficacy by blocking or interfering with the desmoplastic process and enhance tumor penetration, accumulation, and drug distribution. Thus, targeting stroma components of the desmoplastic reaction might be a promising new area of investigation in pancreatic cancer treatment.