Experts Find Why Chemotherapy Fails In Cancer Patients

 A study from Idibell Bellvitge Biomedical Research Institute in Spain has reached a crucial finding for the failure of chemotherapy in colorectal cancer which remains a major obstacle in cancer treatment at present. The team of researchers at the institute claims to have found tumor microenvironment in cases of colorectal cancer that play a pivotal role in making tumor cells resistance against chemotherapy.

These findings, which can have a ground breaking implication in future, were also recently posted in the journalOncotarget.

Chemotherapy remains a conventional treatment to fight off cancers but it largely remains either ineffective or leaves serious adverse effects on the health of cancer sufferers. Recently, studies have surfaced on a global front that have questioned the efficacy of chemotherapy and triggered a debate that foresees a bleak future of chemotherapy as an effective cancer treatment tool.

But with better understanding of cellular pathways and their role in creating chemotherapy resistance in tumor cells, experts can save the decades long work and resources that have gone into developing these chemotherapies.

The importance of tumor microenvironment (TME) has been of the primary focus of the researchers of this study which has induced resistance in the tumor cancers to respond to the chemotherapy.

It was observed that the soluble factors released by the carcinoma-associated fibroblasts (CAFs) trigger the translocation of Akt, Survivin and P38 to the nucleus of tumor cells. Previous studies have shown that CAFs have an integral role in making the tumor microenvironment which facilitates the growth and spread of cancer cells through recruiting different pathways.

While different cancer types have CAFs which are different from one another in nature, showing a high degree of heterogeneity, the potential for CAFs as tumor biomarkers is required to be explored in detail.

However, so far the researchers know that the CAFs are closely linked with the primary tumor cells and they induce processes that slow down the cell cycle and affect the proliferation of tumor cells. When these tumor cells are exposed to chemotherapy, the tumor microenvironment helps to stabilize and activate proteins (through downstreaming, that is reduced gene expression) that minimize the treatment efficacy.

Akt is a serine/threonine kinase and has a role in regulating multiple biological pathways which are involved in cell survival, proliferation, growth and glycogen metabolism.

However, when the expression of Akt gene is expressed during a cell cycle where it is not required (ectopic expression), it can activate oncogenes and increase tumor formation which is chemoresistance.

Primarily, Akt has many primary downstream targets that regulate tumor-associated cell processes, cell cycle progression, survival, migration and angiogenesis. However, a therapeutic target that can block the Akt signaling target can potentially result in the growth inhibition of tumor cells.

Survivin, also known as apoptosis inhibitor 4, is a gene which encodes negative regulatory proteins which prevent apoptotic cell death. Increased gene expression is linked with tumor cells which in turn work as a protective shield against the effects of chemotherapy for malignant cells.

P38, which is also mitogen-activated protein kinase (MAPK), has an array of cellular functions which include cellular proliferation, differentiation, transcription regulation and development.

After getting activated under environmental stresses and by pro-inflammatory cytokine, the triggered pathways play crucial role in cell cycle regulation and tumor suppression. The oxidative stress induces mutations in these kinase genes which regulate tumor genesis i.e., the synthesis of tumor cells.

On the contrary, if the JAK-STAT signaling pathways are inhibited, these tumor growth facilitating effects at the molecular level can be reverted.

To understand this better, here is what these JAK-STAT pathway do. Abbreviated for Janus kinase/signal transducers and activators of transcription, this pathway is a principle signaling mechanism for cell proliferation, differentiation, cell migration and apoptosis.

When encountered with a genetic aberration, this pathway tends to give rise to neoplasm (tumor cells) or at other times activate a number of oncogenes while consequently leading to cancer progression to advanced stages. However, if this pathway is inhibited, the tumor cell proliferation can be slowed down which makes this pathway a current focus of therapeutic interventions.

The researchers, who have been actively studying the resistance of tumor cells to chemotherapy through an extended program by the name of program against cancer therapeutic resistance (PROCURE), have reached crucial findings that carry a potential of changing the landscape of cancer in future.

This notion was equally expressed by the co-researcher Dr Mollevi, who said, “Although current cancer research mainly focuses on therapies against specific targets, most tumors are still treated with conventional cytotoxic therapies, so drug resistance remains the main obstacle to their success.”

This will lead the clinicians to better understand and identify biomarkers that results in microenvironment-mediate drug resistance which in turn can help save millions of lives, globally.

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