Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the “perfect storms” that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects.

Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity

“…Adding to the heterogeneity of cancer cells, signals from stromal cells and extracellular matrix (ECM) components can also promote and maintain cancer stem/stem-like cells (CSCs) (Lu et al 2012; Chanmee et al 2014; Chen et al 2014a; Whatcott et al 2015b). CSCs represent a population of cancer cells thought to be responsible for tumor initiation and progression (Magee et al 2012).…”

“…There is a significant population of CAFs and/or stellate cells (a type of stromal cell), depending on the host organ, that produce and maintain the ECM, which supports the epithelial tissue in carcinomas (Ronnov-Jessen et al 1996; Tlsty and Coussens 2006; Whatcott et al 2015b). These cells are activated as a result of an imbalance of pro- and antifibrotic signaling (Fig.…”

“…As a result, most tumors have hypoxic regions. Hypoxia promotes abnormal angiogenesis (Pugh and Ratcliffe 2003), desmoplasia (Spivak-Kroizman et al 2013), and inflammation (Facciabene et al 2011)—all contributing to tumor progression and treatment resistance (Jain 2014; Whatcott et al 2015b). Thus, once an abnormal vasculature develops (see online Movie 1 at www.cshperspectives.cshlp.org) and leads to a hypoxic microenvironment, a vicious cycle promoting cancer progression and heterogeneity sets in.…”

Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma

“…Pro-fibrotic pathways are known to promote tumor desmoplasia, which acts as a physical barrier to drug delivery and immune cell infiltration(24-26), thus reducing the efficacy of chemotherapy and immunotherapy. Desmoplasia compresses blood vessels and promotes a hypoxic tumor microenvironment which further aggravates immunosuppression(6,27,28).…”

Vitamin D and Myofibroblasts in Fibrosis and Cancer: At Cross-purposes with TGF-β/SMAD Signaling

“…We and others (104)(105)(106)(107) hold the tenable opinion that, in contrast to the ablation and loss of stromal components (108), the reprogramming and re-education of specific TME cell populations, such CAFs, are obviously the most logical and less disrupting approaches to selectively modify TME: in this context, vitamin D reprogramming of the pancreatic stroma (70) by promoting the dedifferentiation of hepatic stellate cells is a salient case in point. Another pertinent example is the reprograming of TME by disruption of the C-C chemokine receptor type 5 (CCR5)-induced homing of regulatory T cells in a mouse pancreatic ductal adenocarcinoma model (109).…”