Lab grown breast cancer cells (MCF-7) treated with hormones and a drug. Image: Dr. K

Invadopodia.

This may sound like invading Extraterrestrials from an Armageddon-esque summer blockbuster. The reality for Earthlings is that invadopodia are not confined to an IMAX theater or season. These are leg-like extensions that protrude from cancer cells, helping them migrate and spread to healthy tissues. This phenomenon is a hallmark of invasive cancers and known as metastasis, which leads to debility and lethality. It is pretty much the point of no return for 90% of those who are afflicted with cancer. Breast cancer is one of the most highly battled and recognized invasive carcinomas.

So, what's the deal with invadopodia and breast cancer metastasis?

A Breakdown of The Basics:

Mammary function is controlled by specialized cells in breast tissue
Cells become compromised by a malfunction
Cell cycle dysregulation ensues
Breast cancer is formed

Growth, invasion, and spreading are the main steps involved in breast cancer formation. Each step is studied individually as the molecular, chemical, and physiological environments change within each stage.

GROWTH:

Malignant cells grow uncontrollably. Why is this a problem in a supersize everything, more-is-more culture? Organs are designed to grow to a specified size range to carry out their assigned functions within an evolutionarily determined area. Limitless growth of cells causes issues for tissues (psst: tissues are a mass of cells) because when tissues grow out of proportion, so do organs (psst deux: organs are made out of tissues). Oversized organs push up on other parts of the body and organs, blocking proper flow and function of the good stuff. This is like getting jammed on the subway during rush hour in the summer -no space to move or breathe.

INVASION:

Invadopodia are on the come up. These mutated super legs are only in the types of cancer cells programmed for metastasis. Certain factors allow invadopodia to grow out of the cell like how your legs extend from your hips. One factor is actin, which is also in muscle cells allowing contraction. Their M.O. is to eat up the material keeping healthy tissues together in order to infiltrate them. So, the deal is to stop these marauders from trudging over and conquering bodies.

SPREADING:

Like a bad apple that ruins the entire bunch, malignant cells take over areas and organs that are far from origination in distance and function. Malfunctioning cells in breast tissue forge cancers of the brain, uterus, bones, and liver. Invadopodia are vital for cancer cell viability. How invadopodia push through and invade surrounding tissues is comparable to how muscles in human legs and peds allow for kicking obstacles out of one’s way. In addition to actin, invadopodia produce supplementary proteins and molecules that help them form, move, and invade.

Ruthless as they are, these sneaky creeps may be stopped with various therapeutics depending on their stage and mechanisms of invasion.

Breakdown of tissue connections and penetration of the tissue must occur for successful invasion and metastasis. ECM (extracellular matrix) degradation with recruited enzymes is equivalent to busting through building foundation, allowing the invading tumor cells to start seeping in like sludge. Stopping the process at this point is essential to impeding metastasis. How enzymes are attracted is unknown, but scientists have been researching what might be able to "amputate” invadopodia.

Invadopodia extending from the cell body of lab grown breast cancer cells (MCF-7). Cells were treated with hormones and a drug. Image: Dr. K

Lab grown breast cancer cells (MCF-7). No treatment and no signs of invadopodia. Image: Dr. K

DRUGS-n-$TUFF:

Biochemical substances, like specific antibodies, can block some of the enzymes that are involved with invadopodia maturation and ECM degradation. Many proteins that are blocked stop formation, degradation, and/or metastasis. For example, deleting a protein called N-WASP stops breast cancer cell metastasis because invadopodia stops developing.

Dasatinib, a leukemia treatment, blocks invadopodia formation in some lab grown breast cancer cell lines by disrupting cell signaling through specific molecules. It is like breaking internal communication within a company, which usually does not equate to successful product output. Of note, other lab cell lines are insensitive to Dasatinib unless a drug combo is used, which explains why effectiveness of treatments differs between people.

The receptors for the hormones estrogen and progesterone are expressed by some breast cancer cells, allowing tumor formation and progression after activation via hormone binding. In the lab, estrogen and progesterone foster invadopodia growth, thus increasing migration of the cells into healthy tissue. In contrast, certain drugs decrease invadopodia despite the presence of estrogen and progesterone because of the effect they have on specialized molecules that regulate estrogen receptor-expressing breast cancer cell function.

Proliferation, invasion, migration, metastasis, or survival in lab grown and triple negative breast cancer cells are blocked by spices like curcumin, black pepper, saffron, coriander, and synthetic flavonoids. Basically, a cell signaling pathway eventually turns off a gene involved in metastasis.

Invadopodia growth after estrogen and drug treatment in lab grown breast cancer cells (MCF-7). Image: Dr. K

Protein expression in lab grown breast cancer cells after hormone treatment. Hormone 1 (H1) and Hormone 2 (H2) have different effects on the expression of Protein 1 (P1) and Protein 2 (P2) when compared to Control (C) cells. Image: Dr. K

GENETIC TIDBITS:

Breast cancer is the unwanted inheritance when BRCA (BReast CAncer susceptibility gene) is unable to suppress tumor formation due to mutations or other abnormalities. Not all breast cancers are due to mutations in the BRCA’s and can be a combination of factors. Actress and philanthropist Angelina Jolie’s genetic screening confirmed that her BRCA1 gene was mutated along with the presence of other cancer-related factors. HER2 is another type of gene that is responsible for breast cancer formation, but not necessarily genetically inherited. When HER2 is over-expressed, there is a boosted aggressive progression because of a change it makes in the breast cancer cell membrane. This modification increases cell proliferation and invasion.

Some non-coding genes (genes that do not get translated into proteins) are responsible for invasion and metastasis. Certain types of RNA’s, like the long non-coding RNA HOTAIR, work and communicate with other components within the cell to tell it to either keep going or stop. Treatments that target either coding or non-coding genes might assist in halting metastasis of breast cancers that are known to be caused by them.

BOTTOM LINE

Co-existence between humans and breast cancer may be light years away. It’s grip is as heavy as an alien life form latching on and taking control of our body. The difficulty in understanding and annihilating this affliction is that it carries a multitude of unresolved facets that manipulates human life. If metastasis can be halted by effectively eliminating invadopodia, then we might have a chance in the battle. Until then Earthlings, stay strong in moving on.

Researchers Who Researched:

Carmona G. et al. (2016) Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene. 35 (39): 5155–5169.

Chung, I. et al. (2016) High cell-surface density of HER2 deforms cell membranes. Nat. Commun. 7: 12742.

Diermeier SD. et al. (2016) Mammary Tumor-Associated RNAs Impact Tumor Cell Proliferation, Invasion, and Migration. Cell Rep. 17 (1): 261–274.

Fairhurst C. et al. (2016) Sodium channelinhibiting drugs and cancer survival: protocol for a cohort study using the CPRD primary care database. BMJ Open 6 (9): e011661.

García, E. et al. (2016) WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Sci. Rep. 6: 23590.

Jolie Pitt, A. “Angelina Jolie Pitt: Diary of a Surgery.” New York Times 24 March 2015: A23. Print.

Paz H. et al. (2014) Invading one step at a time: the role of invadopodia in tumor
Metastasis. Oncogene. 33 (33): 4193–4202.

Pichot CS. et al. (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101 (1): 38-47.

Revach OY and Geiger B. (2014) The interplay between the proteolytic, invasive,
and adhesive domains of invadopodia and their roles in cancer invasion. Cell Adh Migr. 8 (3): 215–225.

Shin, S. Y. et al. (2016) The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt–IKK–NF-κB–MMP-9 axis. Sci. Rep. 6: 34134.

Truong, D. et al. (2016) Breast Cancer Cell Invasion into a Three-Dimensional Tumor-Stroma Microenvironment. Sci. Rep. 6: 34094.

Zheng J. et al. (2016) Spices for Prevention and Treatment of Cancers. Nutrients. 8 (8): 495.