Autophagy supports stromal cells and promotes tumor growth b
3.2.5. Autophagy supports stromal cells and promotes tumor growth
In most cases, tumor cells hijack stromal cell functions and switch on autophagy to maintain homeostasis and support tumor growth (Zhou et al., 2013). During tumorigenesis, cancer cells induce excessive ROS production, which activates oxidative stress response mechanisms and autophagy in stromal cells. Both autophagy activation and the anti-oxidant defense mechanisms in stroma protect the adjacent cancer cells from cellular damage and cell death (Zhou et al., 2013). Increased ROS production in stroma was also associated with another tumorigenic
eﬀect termed as the “Bystander-eﬀect” which results in DNA damage and 120685-11-2 in adjacent cancer cells (Lisanti et al., 2010). Ad-ditionally, autophagy-mediated recycling of energy-rich metabolites in stroma such as the ketones and L-lactate may support mitochondrial biogenesis and anabolic growth of cancer cells (Zhou et al., 2013). In-terestingly, ketones and lactate are reported to function as chemo-at-tractants for cancer cells, which stimulate tumor growth and metastasis.
3.2.6. Autophagy provides resistance to cancer cells
Resistance to chemotherapeutic agents remains a major challenge that limits the eﬃcacy of anticancer drugs. Resistance is developed to anticancer drugs through utilization of several mechanisms such as reduced drug intake, enhanced drug eﬄux by overexpression of certain type of transporters, ineﬃcient drug penetration into the solid tumors (Wu et al., 2014); activation of drug metabolism and/or anti-oxidant metabolism, acquisition of regulatory defects in the apoptotic pathway and/or cell cycle checkpoint control mechanisms, activation of DNA repair machineries to reduce drug-induced DNA damage. Growing evidence indicated that while autophagy contributes to the anticancer eﬃcacy of chemotherapy, it confers drug resistance in several cases (Sui et al., 2013). Similarly, in response to radiation, autophagy is often considered cytoprotective, whereas radiation-induced autophagy has also been found to sensitize the cancer cells to radiotherapy (Sharma et al., 2014). Majority of anti-cancer drugs target programmed cell death mechanisms to kill cancer cells and recent progress in pharma-ceutical research area show that utilization of autophagy-related pro-grammed cell death in cancer therapy can be used as an alternative way to destroy malignant cells (Ouyang et al., 2012).
Autophagy-associated resistance to chemotherapy has become a challenge for cancer treatment. For example, autophagy promoted re-sistance to gefitinib and erlotinib (tyrosine kinase inhibitors) treatment in human lung cancer cells (Han et al., 2011; Jiang et al., 2018). Other examples include, resistance to treatment for imatinib in leukemia (Shingu et al., 2009), temozolomide in glioblastoma (Milano et al.,
Role of autophagic proteins in cancer.
The stress factors mentioned above (nutrient starvation, hypoxia, oxidative stress and DNA-damage) are among the inducers of cell death pathways, including apoptosis. Two major apoptotic pathways play role in execution of cells: extrinsic and intrinsic signaling pathways. The extrinsic (death receptor associated) pathway is induced upon binding of the ligands such as FAS or TNF to cell death receptors. Once acti-vated, these death receptors mediate caspase 8 activation and promote cell death (Galluzzi et al., 2012). The intrinsic (mitochondrial or BCL-2 regulated) pathway, however, can be activated in response to stress factors or chemo/radiotherapies through induction of the pro-apoptotic BCL-2 family proteins. BCL-2 activation promoted permeabilization of the mitochondrial outer membrane and release of cytochrome c into the cytosol (Adachi et al., 1997). However, cancer cells acquired apoptosis-resistance through upregulation of pro-survival factors, such as in-hibitors of apoptotic proteins (IAPs), NF-κB, and the BCL-2 family proteins (Marquez and Xu, 2012). For example, decreased level of apoptosis and resistance to death play a critical role in tumorigenesis of gastric cancer. Long-term scutellarein treatment restored the decreased level of apoptosis in human gastric cancer cells. Scutellarein could successfully inhibited cell proliferation by downregulation of MDM2 and activation of p53 and finally subsequent downregulation of IAPs suggesting the significant anti-tumor role of scutellare in tumorigenesis-associated cell death resistance (Saralamma et al., 2018).
Thus, targeting the autophagy-dependent mechanisms involved in drug resistance and cancer cell survival allow us to develop novel therapeutic strategies to enhance the eﬀects of chemotherapy and im-prove clinical outcomes of treatment in cancer patients (Sui et al.,
Cancer type Protein Phase of autophagy Status in cancer tissue Reference
Tumor suppressor roles
Colorectal carcinomas UVRAG