Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

doi:10.1016/j.canlet.2018.08.008

Cancer Letters

Volume 436, 1 November 2018, Pages 22-27

https://doi.org/10.1016/j.canlet.2018.08.008 Get rights and content

Highlights

•
Tumor microenvironment (TME) governs progression and treatment outcome of pancreatic ductal adenocarcinoma (PDAC).
•
3D hydrogels derived from or inspired by components in the TME are progressively used to recapitulate PDAC tumor matrix.
•
Cell-laden hydrogels can provide relevant compositions, conditions, and contexts for supporting PDAC cell fate processes.
•
This review summarizes recent efforts in using hydrogels for studying cell-matrix or cell-cell interactions in PDAC.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC.

Section snippets

Tumor microenvironment in PDAC

Many solid cancers have cancer cells that exhibit self-sufficiency in growth signals, unlimited cell growth, sustained ability to obtain nutrients, apoptosis resistance, insensitivity to growth inhibitory pathways, and the capacity to invade and metastasize [1]. Pancreatic ductal adenocarcinoma (PDAC) has similar characteristics. PDAC is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8% [2]. These slight increases in survival statistics in

Matrigel®

Matrigel is derived from basement membrane of Engelbreth-Holm-Swarm (EHS) mouse sarcoma and is rich in collagen IV, laminin, heparin sulfate proteoglycans (HSPG), as well as a variety of growth factors. Matrigel solidified/gelled when the temperature is above 10 °C. Because of its tumor origin, Matrigel has been used for culturing a variety of cancer cells in 3D [36,37], including PCCs [38]. For example, Reddy and colleagues showed that pancreatic ductal epithelial cells organized into

3D culture of pancreatic cancer cells with semi-synthetic hydrogels

Hydrogels prepared from synthetic polymers, such as derivatives of poly(ethylene glycol) (PEG), have been used to support the survival of PCCs in 3D [[54], [55], [56]] and to deliver apoptotic/anti-cancer agents to treat PDAC [[57], [58], [59]]. To mimic a cancer cell niche using synthetic hydrogels, it is common to include biomimetic peptides for gel crosslinking and for receptor activation [56,60]. In one example, multi-arm PEG-based macromers (e.g., PEG-norbornene, PEG-maleimide,

Dynamic hydrogels to probe PDAC cell fate

The biochemical compositions and biophysical properties in TME vary greatly depending on the stages of tumor development. The dynamic evolution of stromal tissue stiffness could lead to mechanosensing to both cancer cells and stromal cells. As such, hydrogels capable of recapitulating the dynamic landscape of extracellular microenvironment are of great importance for fundamental understanding of matrix-induced aberrant cell-matrix interactions [62,63]. Recent work has shown that the stiffness

Conclusion and outlook

Cell-laden hydrogels are increasingly used in cancer cell studies. Overall, animal derived matrices are advantageous owing to their inherent biological motifs for cell attachment and invasion. However, the batch-dependent material compositions and properties, as well as residual growth factors could confound the interpretation of the experimental results (Table 1). While gelation of Matrigel is easily achieved through controlling temperature, pre-cooled pipet tips, microtubes, and cell culture

Funding

This work was supported, in part, by National Science Foundation CAREER Award (#1452390) to C.C.L and National Cancer Institute grant (CA-075059) to M.K.

References (73)

D. Hanahan et al.
Hallmarks of cancer: the next generation
Cell
(2011)
J.L. Humphris et al.
Hypermutation in pancreatic cancer
Gastroenterology
(2017)
P.P. Provenzano et al.
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Canc. Cell
(2012)
B.C. Ozdemir et al.
Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival
Canc. Cell
(2014)
A.D. Rhim et al.
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
Canc. Cell
(2014)
M.H. Sherman et al.
Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy
Cell
(2014)
J. Gore et al.
Pancreatic cancer stroma: friend or foe?
Canc. Cell
(2014)
X. Xu et al.
Three-dimensional in vitro tumor models for cancer research and drug evaluation
Biotechnol. Adv.
(2014)
T.V. Nguyen et al.
Sorafenib resistance and JNK signaling in carcinoma during extracellular matrix stiffening
Biomaterials
(2014)
A.M. Gutierrez-Barrera et al.
Establishment of three-dimensional cultures of human pancreatic duct epithelial cells
Biochem. Biophys. Res. Commun.
(2007)

M.A. Shields et al.

Pancreatic cancer cells respond to type I collagen by inducing snail expression to promote membrane type 1 matrix metalloproteinase-dependent collagen invasion

J. Biol. Chem.

(2011)

A. Haage et al.

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Biochem. Biophys. Res. Commun.

(2014)

C.L. Scaife et al.

Synthetic extracellular matrix enhances tumor growth and metastasis in an orthotopic mouse model of pancreatic adenocarcinoma

J. Gastrointest. Surg.: Offic. J. Soc. Surg. Aliment. Tract

(2008)

H. Shih et al.

Modular and adaptable tumor niche prepared from visible light initiated thiol-norbornene photopolymerization

Biomacromolecules

(2016)

C.S. Ki et al.

Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance

Biomaterials

(2014)

A. Raza et al.

The influence of matrix properties on growth and morphogenesis of human pancreatic ductal epithelial cells in 3D

Biomaterials

(2013)

H.J. Byeon et al.

Four-arm PEG cross-linked hyaluronic acid hydrogels containing PEGylated apoptotic TRAIL protein for treating pancreatic cancer

Acta Biomaterialia

(2014)

I. Kim et al.

In situ facile-forming PEG cross-linked albumin hydrogels loaded with an apoptotic TRAIL protein

J. Contr. Release: Official Journal of the Controlled Release Society

(2015)

C.C. Lin et al.

PEG hydrogels formed by thiol-ene photo-click chemistry and their effect on the formation and recovery of insulin-secreting cell spheroids

Biomaterials

(2011)

A. Rubiano et al.

Viscoelastic properties of human pancreatic tumors and in vitro constructs to mimic mechanical properties

Acta Biomaterialia

(2018)

H.Y. Liu et al.

Enzyme-mediated stiffening hydrogels for probing activation of pancreatic stellate cells

Acta Biomaterialia

(2017)

H.Y. Liu et al.

Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma

Biomaterials

(2018)

E. Cambria et al.

Covalent modification of synthetic hydrogels with bioactive proteins via sortase-mediated ligation

Biomacromolecules

(2015)

C.S. Dawes et al.

Enzyme-immobilized hydrogels to create hypoxia for in vitro cancer cell culture

J. Biotechnol.

(2017)

R.L. Siegel et al.

Cancer statistics

(2018)

D.T. Le et al.

Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer

J. Clin. Oncol. Offic. J. Am. Soc. Clin. Oncol.

(2015)

J. Kleeff et al.

Pancreatic cancer

Nat. Rev. Dis. Prim.

(2016)

K.S. Inman et al.

Complex role for the immune system in initiation and progression of pancreatic cancer

World Journal of Gastroenterology

(2014)

D. Goldstein et al.

nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial

J. Natl. Cancer Inst.

(2015)

A.V. Sheahan et al.

Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review

Oncotarget

(2018)

D.K. Andersen et al.

Diabetes Pancreat. Diabetes Pancreat. Canc.

(2017)

G.A. Manji et al.

Current and emerging therapies in metastatic pancreatic cancer

Diabetes

(2017)

L. Rahib et al.

Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States

Canc. Res.

(2014)

D.P. Ryan et al.

Pancreatic adenocarcinoma

N. Engl. J. Med.

(2014)

L.B. Alexandrov et al.

Signatures of mutational processes in human cancer

Nature

(2013)

R.B. Corcoran et al.

STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis

Canc. Res.

(2011)

Cited by (22)

Extracellular matrix mechanobiology in cancer cell migration
2023, Acta Biomaterialia
The extracellular matrix (ECM) is pivotal in modulating tumor progression. Besides chemically stimulating tumor cells, it also offers physical support that orchestrates the sequence of events in the metastatic cascade upon dynamically modulating cell mechanosensation. Understanding this translation between matrix biophysical cues and intracellular signaling has led to rapid growth in the interdisciplinary field of cancer mechanobiology in the last decade. Substantial efforts have been made to develop novel in vitro tumor mimicking platforms to visualize and quantify the mechanical forces within the tissue that dictate tumor cell invasion and metastatic growth. This review highlights recent findings on tumor matrix biophysical cues such as fibrillar arrangement, crosslinking density, confinement, rigidity, topography, and non-linear mechanics and their implications on tumor cell behavior. We also emphasize how perturbations in these cues alter cellular mechanisms of mechanotransduction, consequently enhancing malignancy. Finally, we elucidate engineering techniques to individually emulate the mechanical properties of tumors that could help serve as toolkits for developing and testing ECM-targeted therapeutics on novel bioengineered tumor platforms.
Disrupted ECM mechanics is a driving force for transitioning incipient cells to life-threatening malignant variants. Understanding these ECM changes can be crucial as they may aid in developing several efficacious drugs that not only focus on inducing cytotoxic effects but also target specific matrix mechanical cues that support and enhance tumor invasiveness. Designing and implementing an optimal tumor mimic can allow us to predictively map biophysical cue-modulated cell behaviors and facilitate the design of improved lab-grown tumor models with accurately controlled structural features. This review focuses on the abnormal changes within the ECM during tumorigenesis and its implications on tumor cell-matrix mechanoreciprocity. Additionally, it accentuates engineering approaches to produce ECM features of varying levels of complexity which is critical for improving the efficiency of current engineered tumor tissue models.
Activated fibroblasts in cancer: Perspectives and challenges
2023, Cancer Cell
Activated fibroblasts in tumors, or cancer-associated fibroblasts (CAFs), have become a popular research area over the past decade. As important players in many aspects of tumor biology, with functions ranging from collagen deposition to immunosuppression, CAFs have been the target of clinical and pre-clinical studies that have revealed their potential pro- and anti-tumorigenic dichotomy. In this review, we describe the important role of CAFs in the tumor microenvironment and the technological advances that made these discoveries possible, and we detail the models that are currently available for CAF investigation. Additionally, we present evidence to support the value of encompassing CAF investigation as a future therapeutic avenue alongside immune and cancer cells while highlighting the challenges that must be addressed for successful clinical translation of new findings.
Application of hydrogel-based drug delivery system for pancreatic cancer
2023, Recent Advances in Nanocarriers for Pancreatic Cancer Therapy
Cancer is by far the most challenging and complex disease in the world because of its aggressivity, and it suppresses our immune system, hence making it a major death threat to humans. Pancreatic cancer (PC), being one of the most malignant cancers, has only an overall survival rate of 5%. There are different diagnostic methods, such as biomarkers that are available for PC cancer detection, and imaging methods, such as computed tomography. However, these methods are still inefficient due to their limitations such as low specificity. Various localized treatments such as surgical resection, chemotherapy, and radiotherapy have been able to suppress PC but their therapeutic efficacy is less and each one has a set of drawbacks. For example, surgical resection can be performed only on a certain number of patients who are eligible depending upon the stage of cancer and so on. Popular drugs that are available for PC treatment such as gemcitabine even when combined with nanoparticles have limitations such as poor bioavailability and poor specificity of the target tissue site. The discovery of hydrogels has been a great advantage for cancer treatment. Hydrogels attract a lot of attention because of their biocompatibility, bioavailability, and drug-delivering ability at a specific target site. Hydrogels are 3D networks that consist of pores in their hydrophilic structure that swell up when immersed in water and they have the unique ability to release the drug in a controlled and sustained manner. Hydrogels can also be combined with detection techniques such as endoscopic ultrasound (EUS) in order to provide better visualization for PC diagnosis and future treatments. In this chapter, we focus on different kinds of hydrogels, their preparation, their usage in detection purposes, the ways by which they can be used to deliver the drug to the target tumors, and how they can be of a potential cure to PC cancer management.
Different combination therapies pertaining to pancreatic cancer
2023, Recent Advances in Nanocarriers for Pancreatic Cancer Therapy
Pancreatic cancer (PC) is considered one of the lethal malignancies worldwide with a poor prognosis and a median survival rate of 10% in affected persons in a period of several years (about 5 years). Despite recent advancements, effective treatment for PC has remained elusive. A potentially more serious problem is that monotherapies usually cause the intensification of drug resistance with the low effectiveness of the active substance and also metastasis or recurrence of the tumor after the chemotherapy process. A potential way to make the treatment process more effective and decrease side effects is using the combination or multicomponent treatment approach. Codelivery systems along with different therapeutic nanoplatforms lead to an increase in desired response or achieving synergistic-combination results compared to a single drug strategy. Recently, multidrug combination therapy along with the nano-structures of the smart drug delivery systems to PC therapy is widely applied in clinical practice.
In the current chapter, a concise description of some different modes of multidrug combination therapy, including the design of formulations containing natural compounds along with conventional anticancer drugs in different nano-carriers were introduced. This study can be considered an encouraging and potential approach to PC treatment with minimizing the adverse effects associated with conventional chemotherapy.
Advances in bioengineering pancreatic tumor-stroma physiomimetic Biomodels
2022, Biomaterials
Citation Excerpt :
Matrigel is a complex protein mixture derived from the basement membrane of Engelbreth-Holm-Swarm (EHS) mouse sarcoma. Such protein cocktail is rich in collagen IV, laminin, heparin sulfate proteoglycans, as well as a variety of growth factors (e.g., TGF-β, FGF, epidermal growth factor (EGF), PDGF) that constitute the original TME from which this processed basement membrane is derived from [89,117]. Due to its biological origin, Matrigel-based scaffolds have been widely exploited for engineering 3D in vitro PDAC models for investigating cells invasion potential and anti-cancer drugs efficacy, among other applications [89].
Pancreatic cancer exhibits a unique bioarchitecture and desmoplastic cancer-stoma interplay that governs disease progression, multi-resistance, and metastasis. Emulating the biological features and microenvironment heterogeneity of pancreatic cancer stroma in vitro is remarkably complex, yet highly desirable for advancing the discovery of innovative therapeutics. Diverse bioengineering approaches exploiting patient-derived organoids, cancer-on-a-chip platforms, and 3D bioprinted living constructs have been rapidly emerging in an endeavor to seamlessly recapitulate major tumor-stroma biodynamic interactions in a preclinical setting. Gathering on this, herein we showcase and discuss the most recent advances in bio-assembling pancreatic tumor-stroma models that mimic key disease hallmarks and its desmoplastic biosignature. A reverse engineering perspective of pancreatic tumor-stroma key elementary units is also provided and complemented by a detailed description of biodesign guidelines that are to be considered for improving 3D models physiomimetic features. This overview provides valuable examples and starting guidelines for researchers envisioning to engineer and characterize stroma-rich biomimetic tumor models. All in all, leveraging advanced bioengineering tools for capturing stromal heterogeneity and dynamics, opens new avenues toward generating more predictive and patient-personalized organotypic 3D in vitro platforms for screening transformative therapeutics targeting the tumor-stroma interplay.
Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma
2022, Matrix Biology Plus
Citation Excerpt :
Basement membrane extract was used for the 3D culturing of the cells as it is a commonly used hydrogel or scaffold for 3D cell culture, including pancreatic cancer cells [36,37,90,91]. Basement membrane was chosen to allow the cells to naturally engineer an environment (as opposed to the use of a synthetic hydrogel, which often lacks the presence of structured proteins and fail to capture the biophysical structures and cues of the cellular microenvironment) [92–94]. The PSC only, PANC-1 only and PDAC cultures were grown with 10 ng mL−1 of TGF-β1 growth factor supplement (Sigma-Aldrich) [60,95,96] in DMEM/10% FBS culture medium under humidified conditions at 37 °C with 5% CO2 for mechanical stiffness assessment.
Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-β (TGF-β). However, there are few in vitro PDAC models, which include both PSCs and TGF-β or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-β, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment.

View all citing articles on Scopus

View full text

Mini-reviewDesigner hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

Highlights

Abstract

Section snippets

Tumor microenvironment in PDAC

Matrigel®

3D culture of pancreatic cancer cells with semi-synthetic hydrogels

Dynamic hydrogels to probe PDAC cell fate

Conclusion and outlook

Funding

Cell

Gastroenterology

Canc. Cell

Canc. Cell

Canc. Cell

Cell

Canc. Cell

Biotechnol. Adv.

Biomaterials

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Gastrointest. Surg.: Offic. J. Soc. Surg. Aliment. Tract

Biomacromolecules

Biomaterials

Biomaterials

Acta Biomaterialia

J. Contr. Release: Official Journal of the Controlled Release Society

Biomaterials

Acta Biomaterialia

Acta Biomaterialia

Biomaterials

Biomacromolecules

J. Biotechnol.

Cancer statistics

Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer

J. Clin. Oncol. Offic. J. Am. Soc. Clin. Oncol.

Pancreatic cancer

Nat. Rev. Dis. Prim.

Complex role for the immune system in initiation and progression of pancreatic cancer

World Journal of Gastroenterology

nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial

J. Natl. Cancer Inst.

Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review

Oncotarget

Diabetes Pancreat. Diabetes Pancreat. Canc.

Current and emerging therapies in metastatic pancreatic cancer

Diabetes

Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States

Canc. Res.

Pancreatic adenocarcinoma

N. Engl. J. Med.

Signatures of mutational processes in human cancer

Nature

STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis

Canc. Res.

Mini-review
Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment