**7. Stromal cells and clinical therapy**

Stromal cells have therapeutic potential in cancer treatment and targeting stromal components in combination with cancer cells may increase the efficacy of cancer therapy [4, 6]. Stromal signatures characteristic of different cancer subtypes may have clinical relevance and may even serve as a prognostic marker of the disease.

### *Stromal Cells and Extracellular Vesicles DOI: http://dx.doi.org/10.5772/intechopen.106721*

Previously, chemotherapeutic agents were used to target all cells within the tumour microenvironment however, efficacy of these therapies is reduced by the development of drug resistance [7, 59]. Drug resistance occurs primarily by activation or mutation of signal transducers downstream of the targeted molecule or secondarily when neoplastic cells originally sensitive to these drugs lose their response to drugs [6, 8, 59]. In recent years, advancement in therapeutic targeting of the tumour microenvironment has led to specific targeting of cells within the tumour microenvironment. Poorly vascularised stroma supports tumorigenesis and simultaneously forms a barrier for chemotherapeutic drugs making it as an attractive drug target [6, 8]. Since tumours require endothelial cells to form new blood vessels to help relieve oxygen deprivation and accumulate metabolic wastes, angiogenesis is one of the mechanisms targeted by chemotherapy.

Most of these drugs such as bevacizumab, aflibercept, sorafenib and ramucirumab target the VEGF-VEGF signalling pathway in diverse ways as this is associated with tumour progression and poor prognosis in breast cancer [7, 8, 51, 58]. Bevacizumab acts a neutralising antibody to VEFG that reduces vascular permeability thus affecting the first step of tumour stroma development however aflibercept acts a decoy receptor for VEGF. Sorafenib acts a tyrosine kinase inhibitor and ramucirumab acts as an antibody that blocks VEGF from binding to its receptor. However, these chemotherapeutic agents have shown limited success when administered to patients as a single agent. Most patients develop resistance or do not respond to this anti-angiogenic therapy. Metastatic tumour cells have a striking feature/ability to plastically adapt to different microenvironmental conditions and overcome a singledrug treatment [7, 8, 51, 58, 66].

To enhance success within the clinical settings, combination of these drugs or other drugs/approaches may likely prove to be beneficial. For example, combination of bevacizumab and PDL1 proved to be a success in the treatment of hepatocellular carcinoma and renal cancer [7]. Combination therapies targeting thyroid cancer cells and stroma may also offer treatment alternatives as there have been no convincing clinical studies that show the efficacy of tumour stroma inhibition in the most aggressive forms of thyroid cancer.

In addition, an antibody that blocks IL-8 has also been trialled to target the tumour-promoting effect of endothelial cells in glioblastoma with success [6, 23, 31]. This led to a marked reduction in tumour size. Other researchers have also shown that inhibition of IL-8 re-sensitised tumour cells to chemotherapeutic agents, cisplatin, and paclitaxel [6, 31]. Furthermore, CCL5 and IL-6 have also been shown to be associated with acquisition of chemoresistance [6, 31]. These suggest that these cytokines as well as other ligands of CXC chemokine receptors 1 and 2 could be very important in the induction of chemoresistance via recruitment of MSCs around the tumour. In addition, EGF secreted by endothelial cells has been associated with drug resistance in squamous cell carcinoma [6]. Nevertheless, there are very few existing FDA-approved treatments with limited efficacy, but new therapeutic targets and strategies will be identified as researchers continue to understand how the tumour microenvironment contributes to tumour progression and metastasis. There is potential for the use of chimeric antigen receptor natural killer cells, liver stellate cells and fibroblasts [7, 51].

In addition, CAFs may be novel and attractive targets for cancer therapy. CAFs also show the strongest expression level of the stem/mesenchymal transcription subtype of cancer. The crosstalk between CAFs and cancer stem cells is a convincing strategy for immune suppression, drug resistance, metastasis and stemness of cancer cells [6, 23]. CAFs secrete TGF-β and HGF that contribute to drug resistance in tumour cells, including tamoxifen-associated resistance in breast cancer cells [6, 23]. As a result, some novel drugs target the interaction between CAFs and breast cancer cells as it is believed that CAFs increase interstitial pressure within the tumour thereby reducing the efficacy of drug delivery [6, 23, 66]. Also, pirfenidone, which is an anti-fibrotic agent with multiple functions including anti-TGF-β activity, was combined with doxorubicin to inhibit tumour growth and metastasis in a preclinical triple-negative breast cancer (TNBC) model [6, 23].

Targeting CAFs may affect other stromal cells such as polarising tumour-associated macrophages (TAM) and cause suppression of the cytotoxic activities of NK cells since CAFs are involved in promoting immunosuppression [23]. Partial depletion of stroma using CD40-activated macrophages has shown to improve patient survival and increase drug delivery into the tumour [6]. CAFs-induced EMT causes resistance to cisplatin in non-small-cell lung carcinoma [6, 28, 51]. Therefore, a build of CAFs in the tumour microenvironment is associated with poor prognosis in many cancers, including lung adenocarcinoma, squamous cell carcinoma and colorectal cancer, where it is associated with diseases reoccurrence [6, 23, 51]. However, these cells are associated with improved prognosis and overall survival in small lung cell carcinoma. Some researchers have illustrated that targeting Hedgehog-activated CAFs results in improved survival, chemosensitivity and reduced metastatic burden in breast cancer [6, 67].

However, depleting CAFs is not always beneficial and has been associated with increased angiogenesis and enhanced cancer cell properties in pancreatic cancer with shorter patient survival. Hence, these suggest that therapeutic targeting of these CAFs may ameliorate some cancers. Furthermore, the expression of CD44 on CAFs can be functional target for destroying cancer cells in the TME and TGF-β signalling mediated by CAFs plays a role in regulating cancer cells in gastric cancer. Inactivating CAFs or lowering the level of infiltrating CAFs in the TME are potential therapeutic strategies for reducing cancer stemness. Targeting myofibroblast-like CAFs using focal adhesion kinase (FAK) inhibitor resulted in a reduction of pancreatic cancer cells [6]. CAFs can also be targeted by inhibiting their activation by using drugs to target CAF-associated proteins such as fibroblast activation protein (FAP) and DNA methyltransferase 1 (DMNT1) [6]. Sibrotuzumab, a FAP-targeting antibody has been tested in the treatment of Phase II metastatic colorectal cancer whilst combination of DNMT1 and DNMT1 and Janus Kinase (JAK) signalling resulted in the normalisation of fibroblasts, but these failed to demonstrate efficacy [6, 8, 31]. Thus, it is noteworthy to mention that identifying and targeting fibroblasts is problematic due to heterogeneity of markers found on these cells. This, identifying CAFs aid define activate stroma borders and may even affect clinical response to treatment.

Furthermore, interaction between adipocytes and cancer cells has been therapeutically targeted using BMS309403, a FABP4-specific inhibitor in breast cancer [6]. The results revealed a reduction in tumour growth with changes in secretion of IL-6 and ALDH1 expression. Another drug, anti-leptin blocking peptide, impeded the migration of ovarian cancer cells thereby suggesting antibodies against leptin may be an effective therapy for different cancers, including breast cancer [6]. An agonist of Farnesoid X, GW4064, also decreases the signalling of leptin whilst doxorubicin and pirfenidone have been combined to reduce the progression and motility of tumours in the ECM components by inhibiting the production of collagen [6]. Decreased collagen production has also been induced by vaccination, which sensitises fibroblasts to CD8 T-cell attack thereby significantly increasing the uptake of chemotherapeutic drugs.

### *Stromal Cells and Extracellular Vesicles DOI: http://dx.doi.org/10.5772/intechopen.106721*

Furthermore, stromal cells also play an important role in regenerative therapy as well as haematopoietic stem cell transplantation (HSCT), which is the major treatment for cancer where they enhance HSC engraftment and prevent graft-versus-host disease (GVHD) [4, 8]. GVHD is a major complication of HSCT in the treatment of haematological malignancies. GVHD is caused by an attack on recipient tissues by transplanted immune cells.
